Clinical trial NCT05470517
Conditions: Complicated Appendicitis Acute Appendicitis
Sponsor: Johns Hopkins All Children's Hospital
Start date: 2023-01-05; Completion date: 2024-03-20
Enrollment: 190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Appendicitis (inflammation of the wall of the appendix, causing pain and tenderness in the abdomen) has a range of severity that goes from simple to complicated. Complicated appendicitis may present with infected fluid inside of the abdomen or a perforation or hole in the intestines.

This research is being done to determine if placing an antibiotic solution in the abdomen at the time the appendix is removed is a safe procedure in patients between the ages of 3 and 18 years old with findings of complicated appendicitis.

Johns Hopkins All Children's Hospital (JHACH)'s current standard of care for patients with complicated appendicitis includes suctioning the infected fluid out of the abdomen at the time the appendix is removed. As part of this study, the investigators would like to see if patients with complicated appendicitis will benefit from routine care plus leaving an antibiotic solution inside the abdomen, after fully suctioning the infected fluid out of the abdomen.

Detailed description:
Appendicitis is one of the most common surgical diagnoses in the pediatric population and the most common surgical emergency in children. In complex appendicitis, the sequelae have progressed beyond the confines of the organ, and have led to purulent fluid in the intra-abdominal space, spillage of intestinal contents, or gross perforation of the appendix. Complicated appendicitis occurs in up to 20% of cases and is associated with a much higher morbidity and mortality. Previous studies have shown that local treatment of peritonitis associated with peritoneal dialysis (PD) catheters with intra-peritoneal antibiotics has had significant improvement of outcomes. The intra-peritoneal route is preferable as compared to oral and intravenous antibiotic administration due to elevated local levels of the antibiotic above the minimum inhibitory concentration while avoiding venipuncture and systemic side effects. There is minimal risk associated with involvement in this study given that the investigators will be screening for any history of allergies to penicillin or cephalosporins, and excluding these patients. Ceftriaxone is commercially available, has a low risk profile, and is generally well tolerated with minimal side effects.

The investigators' treatment period will include a one-time intra-operative dose of intra-peritoneal ceftriaxone (or an appropriate second or third generation cephalosporin to be designated at the discretion of the institutional Antibiotic Stewardship committee should ceftriaxone be unavailable). Typical dosing strategies for intra-peritoneal ceftriaxone administration occur on a daily basis, so the investigators' treatment period will also include the 24 hours following intra-peritoneal administration of ceftriaxone. All patients diagnosed with acute complicated appendicitis intra-operatively, and entered into the investigators' study, will also receive a minimum 48 hours of intravenous antibiotics as an inpatient, allowing for continued observation. The investigators will be treating pediatric patients who are intra-operatively diagnosed with complex appendicitis, as defined by any of the following: visible hole in the appendix, extra-luminal fecalith, diffuse fibropurulent exudate outside the right lower quadrant (RLQ)/pelvis, or intraperitoneal abscess. All patients will have been admitted to Johns Hopkins All Children's Hospital with a diagnosis of acute appendicitis prior to surgical intervention. Patients will then be randomized once diagnosed with complex appendicitis intra-operatively. Patients with allergies to penicillin or cephalosporins will be excluded pre-operatively, as well as patients who do not meet the weight requirement, are pregnant, being treated non-operatively, and those who have been intra-operatively diagnosed with simple appendicitis.

Arms: arm 1: Intra-operative aspiration of intra-peritoneal fluid after successful appendectomy. arm 2: Intra-operative aspiration of intra-peritoneal fluid after successful appendectomy and subsequent instillation of 10ml of intra-peritoneal ceftriaxone (2g)
Interventions: intervention 1: Ceftriaxone intervention 2: Intra-peritoneal Fluid Aspiration
Intervention descriptions: intervention 1: Ceftriaxone is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous, intramuscular, or intra-peritoneal administration.

Ceftriaxone is a white powder, which is soluble in water. In this study ceftriaxone crystalline powder will be dissolved in 0.9% sodium chloride solution prior to intra-peritoneal instillation.

Antibiotic instillation will be introduced into the RLQ/pelvis after the appendectomy is completed and all intra-peritoneal fluid is aspirated. Ceftriaxone solution will be used depending on availability and pharmacy stock for use at Johns Hopkins All Children's Hospital. The ceftriaxone powder (2g) will be dissolved in 9ml of sterile normal saline, for a total instillation volume of 10ml. This fluid will then be instilled and left to dwell in the area of the peritoneal cavity where the appendix was removed. intervention 2: Intra-operative aspiration of intra-peritoneal fluid after successful appendectomy.

Protocol documents:
Prot_SAP_000.pdf: 
Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 1 of 25 
 
 
 
 
 
Antibiotic Instillation in Acute Complex Appendicitis for Prevention of Deep Space Surgical Site 
Infections 
Antibiotic Instillation in Appendicitis  
 
 
 
 
 
Principal Investigator 
Dr. Nicole Chandler 
Associate Professor, Department of Surgery 
Johns Hopkins School of Medicine 
St. Petersburg, FL 
Phone: 727-767-4170 
Fax: (727) 767-4346 
Email: nicole.chandler@jhmi.edu 
 
 
 
ClinicalTrials.gov Number 
NCT05470517 
 
 
 
 
 
 
Historical Protocol Versions 
Version 1: May 9, 2022 
Version 2: September 20, 2022 
Version 3: October 5, 2022 
Version 4: November 29, 2022 
Version 5: September 27, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 2 of 25 
 
 
 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
       PAGE 
EXPERIMENTAL SCHEMA 
 
 
 
 
 
 
 
4 
PROTOCOL SIGNATURE PAGE 
 
 
 
 
 
 
6 
 
STUDY SUMMARY 
 
 
 
 
 
 
 
 
7 
1. OBJECTIVES 
 
 
 
 
 
 
 
 
 
8 
1.1. Primary Objectives and Endpoints  
 
 
 
 
 
8 
1.2. Secondary Objectives and Endpoints 
 
 
 
 
 
8 
2. BACKGROUND AND RATIONALE  
 
 
 
 
 
8 
2.1. Benefit/Risk Assessment 
 
 
 
 
 
 
 
10 
3. DRUG INFORMATION 
 
 
 
 
 
 
 
11 
4. STUDY DESIGN 
 
 
 
 
 
 
 
 
11 
4.1. Number of Participants 
 
 
 
 
 
 
 
13 
4.2. Number of Study Centers 
 
 
 
 
 
 
 
13 
4.3. Study Duration 
 
 
 
 
 
 
 
 
13 
5. ELIGIBILITY CRITERIA 
 
 
 
 
 
 
 
13 
5.1. Inclusion Criteria 
 
 
 
 
 
 
 
 
13 
5.2. Exclusion Criteria 
 
 
 
 
 
 
 
 
14 
6. ENROLLMENT GUIDELINES 
 
 
 
 
 
 
14 
6.1. Screen Failures 
 
 
 
 
 
 
 
 
14 
7. ANTIBIOTIC INSTILLATION INTERVENTION PLAN  
 
 
14 
7.1. Intervention Schedule 
 
 
 
 
 
 
 
14 
7.2. Third Generation Cephalosporin Intra-peritoneal Instillation Treatment 
 
15 
7.3. Prohibited Concomitant Medications 
 
 
 
 
 
15 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 3 of 25 
 
7.4. Duration of Therapy/Intervention 
 
 
 
 
 
 
 
15 
7.5. Lost to Follow Up 
 
 
 
 
 
 
 
 
 
16 
8. TOXICITIES AND DOSEAGE MODIFICATION  
 
 
 
 
16 
8.1. Adverse Events (AEs) 
 
 
 
 
 
 
 
 
16 
8.2. Serious Adverse Events (SAEs) 
 
 
 
 
 
 
 
17 
8.3. Unanticipated Problems Involving Risks to Participants or Others (UPIRPO) 
 
18 
8.4. Reporting Requirements 
 
 
 
 
 
 
 
 
18 
8.5. Supportive Care 
 
 
 
 
 
 
 
 
 
18 
9. STUDY CALENDAR 
 
 
 
 
 
 
 
 
 
19 
10. STUDY PROCEDURES 
 
 
 
 
 
 
 
 
19 
11. CRITERIA FOR EVALUATION AND ENDPOINT  
 
 
 
 
20 
11.1. 
Efficacy 
 
 
 
 
 
 
 
 
 
20 
12. STATISTICAL CONSIDERATIONS  
 
 
 
 
 
 
20 
13. DATA SUBMISSION SCHEDULE 
 
 
 
 
 
 
 
22 
14. ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
 
 
22 
14.1. 
Informed consent 
 
 
 
 
 
 
 
 
22 
14.2. 
Institutional Review  
 
 
 
 
 
 
 
23 
14.3. 
Protocol Amendments 
 
 
 
 
 
 
 
23 
14.4. 
Protocol Deviations  
 
 
 
 
 
 
 
23 
14.5. 
FDA Annual Reporting 
 
 
 
 
 
 
 
23 
14.6. 
Clinical Trials Data Bank 
 
 
 
 
 
 
 
23 
14.7. 
Record Keeping 
 
 
 
 
 
 
 
 
23 
15. BIBLIOGRAPHY 
 
 
 
 
 
 
 
 
 
24
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 4 of 25 
 
 
EXPERIMENTAL SCHEMA 
 
 
 
Standard of Care 
Treatment for 
Acute 
Appendicitis 
Minimum 48hr of IV 
Ceftriaxone and 
Metronidazole 
Daily physical exam, 
vitals, diet 
advancement per 
surgeon discretion 
POD7 Imaging if not 
meeting discharge 
criteria and no other 
medical reason for 
hospitalization 
Discharge Home Pending: 
-
Minimum of 48hr IV antibiotics 
-
Temperature <38.5C 
-
Minimal abdominal pain 
without use of narcotics 
-
Tolerance of enteral intake 
Diagnosis of 
Appendicitis 
and ≥20kg in 
weight 
Consent for 
study 
Suction ONLY  
Enrolled and 
Randomization 
Suction and 
100mg/ml 
Ceftriaxone 
(1g in 9ml of 
0.9%NS) 
instillation 
Completion of 
Appendectomy 
Operating room findings of Complicated 
Appendicitis (at least one below): 
-
Visible hole in appendix 
-
Diffuse fibropurulent exudate 
(outside of RLQ or pelvis) 
-
Intra-abdominal abscess 
-
Extra-luminal fecalith 
If no OSI  PO Abx for total course of 10 
days 
  
If OSI, antibiotics at DC based on 
surgeon discretion  
Discharge 
home  
Follow up within 30 
days in clinic or via 
phone or mail 
Yes 
No 
Yes 
No 
Non-
complicated 
appendicitis 
treatment  


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 5 of 25 
 
 
Figure 1: Standardized treatment protocol including study inclusion criteria and discharge checklist.    
 
 
Minimum 48hr of IV 
Ceftriaxone and 
Metronidazole 
Daily physical exam, 
vitals, diet 
advancement per 
surgeon discretion 
POD7 Imaging if not meeting discharge 
criteria and no other medical reason for 
hospitalization 
Discharge Criteria: 
-
Minimum of 48hr IV antibiotics 
-
Temperature <38.5C 
-
Minimal abdominal pain without 
use of narcotics 
-
Tolerance of enteral intake 
Diagnosis of Appendicitis 
Consent for study 
Suction ONLY  
Suction and 
Ceftriaxone 
instillation 
OR for Appendectomy  
Completion of 
Appendectomy 
Operating room findings of Complicated 
Appendicitis (at least one below): 
-
Visible hole in appendix 
-
Diffuse fibropurulent exudate 
(outside of RLQ or pelvis) 
-
Intra-abdominal abscess 
-
Extra-luminal fecalith  
If no OSI  PO Abx for 
total course of 10 days 
  
If OSI, antibiotics at 
DC based on surgeon 
discretion  
 
Discharge 
home  
Follow up within 30 
days in clinic or via 
phone or mail 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 6 of 25 
 
 
PROTOCOL SIGNATURE 
 
I confirm that I have read and understood this protocol, and I will conduct the study as outlined 
herein and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable laws and 
regulations of the federal government.  I will promptly submit the protocol to the IRB for review and 
approval.  Once the protocol has been approved by the IRB, I understand that any modifications 
made during the course of the study must first be approved by the IRB prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me 
who assist in the conduct of this study.  I will discuss this material with them to ensure that they are 
fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
 
 
 
 
 
 
 
 
 
___________________________________  
_______________ 
Signature of Principal Investigator  
 
Date 
 
 
Nicole Chandler, MD 
____________________________________ 
Principal Investigator Name (Print) 
 
 
Johns Hopkins All Children’s Hospital 
____________________________________ 
Name of Institution 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 7 of 25 
 
STUDY SUMMARY 
 
Title 
Antibiotic Instillation in Acute Complex Appendicitis for 
Prevention of Deep Space Surgical Site Infections 
Short Title 
Antibiotic Instillation in Appendicitis  
IND 
IND 
Phase 
Pilot Phase 2 
Design 
Randomized single blind control study 
Study Duration 
1 year 
Study Center(s) 
Single-center 
Objectives 
The primary objective is to evaluate the feasibility and 
safety of the use of antibiotic instillation in the treatment of 
complex acute appendicitis measured by enrollment rates 
and ability to complete all study tasks. Secondary 
objectives are to examine the rate of intra-abdominal 
abscess formation and post-operative length of stay 
following treatment of complex appendicitis in the setting 
of appendectomy with intra-operative suction alone 
compared to suction with intra-peritoneal antibiotic 
instillation  
Number of Participants 
A total of 36 patients will be randomized to two groups in 
this pilot study 
Diagnosis and Main Eligibility 
Criteria 
Intraoperative diagnosis of complex appendicitis defined 
by: a visible hole in the appendix, extra-luminal fecalith, 
diffuse fibropurulent exudate (outside the right lower 
quadrant (RLQ)/pelvis) or presence of intra-peritoneal 
abscess 
Study Product, Dose, Route, 
Regimen 
Ceftriaxone, >20kg (1g in 9ml of 0.9% normal saline), 
intraperitoneal instillation given once following 
appendectomy, and aspiration of excess intra-peritoneal 
fluid 
Duration of Administration 
A one-time dose of intra-peritoneal ceftriaxone solution 
following appendectomy 
Reference Therapy 
Standard of care is intra-peritoneal aspiration alone, or 
irrigation of the peritoneal cavity with or without antibiotic 
in the irrigant fluid. 
Statistical Methodology 
Descriptive statistics will be used to summarize the results. 
Continuous variables will be summarized using means and 
standard deviation or median and range as appropriate. 
Categorical variables will be summarized using counts and 
percentages. Data will be presented using tables and 
figures 
 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 8 of 25 
 
1 
OBJECTIVES 
 
1.1.1 Primary objective 
 
To evaluate the feasibility and safety of the use of antibiotic solution instillation 
following intraoperative diagnosis of complex appendicitis. We will determine 
feasibility by the percentage of eligible participants who (1) agree to participate, and 
(2) complete all intervention sessions and measurement time points. Safety will be 
evaluated by adverse events associated with the use of intra-peritoneal antibiotic 
instillation for the treatment of peritonitis caused by complex appendicitis. 
1.1.2 Secondary objectives 
A. To evaluate preliminary efficacy of antibiotic solution instillation following 
diagnosis of complex appendicitis.  
B. To compare the following outcomes between patients who receive or do not 
receive antibiotic solution instillation following diagnosis of complicated 
appendicitis: operative time, length of stay, post-operative antibiotic use, post-
operative pain medication use, need for post-operative imaging, readmission rates, 
and the development of intra-peritoneal abscess requiring percutaneous aspiration 
and/or drainage within 30-days following appendectomy. 
2 
BACKGROUND AND RATIONALE 
Appendicitis is the most common abdominal surgical emergency in children, affecting 
approximately 75,000 children a year.[1, 2] Mitigating the associated morbidities of this disease 
process is of paramount concern to the pediatric surgeon.[1] In complicated or complex appendicitis, 
the infectious process is noted to have progressed beyond the confines of the appendix, which leads 
to purulent fluid in the intra-peritoneal space (diffuse exudate outside of the right lower quadrant 
(RLQ)/pelvis), a visible hole (perforation) of the appendix, an extra-luminal fecalith, or an intra-
peritoneal abscess. Complex appendicitis occurs in up to 20% of all cases of appendicitis and is 
associated with a much higher morbidity and mortality than its simple counterpart.[1, 3-5] 
The ensuing systemic response from complex appendicitis has a significant impact on the 
patient and their families. Complex appendicitis results in significant morbidity, with increased rates 
of intra-peritoneal abscess formation, and surgical site infections, as well as increased length of stay. 
[6, 7] The increased inflammation and bacterial insult can result in urinary retention, diarrhea, 
increased pain, and a high incidence of deep organ space infection. [6] In the peritoneal space, 
infection can progress to form an intra-abdominal abscess, which is treated with intravenous 
antibiotics and often percutaneous or operative drainage. All of these factors in combination with the 
increased level of systemic insult experienced by the patient, correlate with longer and more costly 
hospital stays, increased need for advanced imaging leading to more radiation exposure, prolonged 
antibiotic use, and increased discomfort and generalized malaise, more time away from school, 
work, and home. 
Current management strategies for intra-operatively diagnosed complex appendicitis include 
appendectomy with aspiration of infected intra-peritoneal fluid followed by continued post-operative 
treatment with intravenous or oral antibiotic therapy.[8] Previous studies have not seen dramatic 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 9 of 25 
 
improvements with antibiotic irrigation, large volume irrigation, or prophylactic intra-peritoneal 
drain use to prevent intra-abdominal abscess formation.[9-18] As such, the search continues to find 
an answer to the high rate of deep space infection associated with complex appendicitis, which can 
be as high as 45%.[5, 19]  
Interventions to counter these negative effects currently focus on the aftermath of an intra-
abdominal abscess and how to manage it once it has been identified. Previous studies have 
investigated the use of peritoneal irrigation solutions (with or without antibiotics) at the time of 
surgery, in hopes of decreasing intra-abdominal abscess rates and length of stay following 
appendectomy, but these studies did not show any significant improvement in abscess rates after 
irrigation compared to aspiration alone.[5, 18, 20] These previous studies may not have observed an 
improvement in post-operative complications given that they did not allow for the antibiotic solution 
to remain in the intraperitoneal space.  
The current pilot project focuses on assessing the feasibility of using antibiotic instillation to 
prevent deep organ space surgical site infection, which would be a significant improvement to the 
existing standard of care. Currently there is no literature that describes utilizing antibiotic instillation 
in the treatment of complicated appendicitis, thus this pilot study will provide important feasibility 
data prior to instituting a large multicenter trial.  Pending feasibility of our pilot study, our project 
will further study the length of stay, and potential prevention of intra-abdominal abscess. The 
outcomes of this limited efficacy testing will be an important initial step to designing a larger, 
multicenter trial which is powered to show improved postoperative outcomes with decreased 
postoperative abscess formation in complicated appendicitis.  
We believe that after appendectomy and removal of the nidus of disease, the post-operative 
field would benefit from treatment with an antibiotic instillation, a solution placed in the peritoneal 
cavity in direct contact with the contaminated surfaces. By leaving the antibiotic solution in place at 
time of closure, the contaminated areas are topically treated with prolonged exposure to the 
bactericidal effects of ceftriaxone (). This technique will give appropriate temporal contact of the 
medication to the bacteria, allowing for better dispersion, and optimized efficacy.  
In patients with peritoneal dialysis catheters, infection of these catheters can lead to 
peritonitis, or inflammation of the peritoneal cavity, which, in turn can progress to sepsis. Peritonitis 
associated with infected peritoneal dialysis catheters is treated with antibiotic instillation into the 
peritoneal cavity with demonstrated success and is currently considered the standard of care 
treatment.[21-24] Intra-peritoneal antibiotic instillation is the current standard of care for treatment 
of peritonitis associated with PD catheters.[25] Given that intra-peritoneal antibiotic instillation is 
the standard of care for PD catheter associated peritonitis, it should also be safe to use for any type 
of peritonitis, and in this case, peritonitis due to complicated appendicitis.  
Recently, the treatment regimens have shifted away from continuous use of antibiotic 
instillations during PD sessions and have moved towards intermittent antibiotic instillations with 
daily dosing.[26, 27] The International Society for Peritoneal Dialysis (ISPD) recommends at least a 
6 hour dwell time for intermittent antibiotic instillation to allow for adequate absorption.[25] The 
ISPD guidelines also suggest that cephalosporins be administered on a daily intermittent basis, or 
continuously (with each exchange), as there is no significant difference in peritonitis treatment 
outcomes with these dosing regimens.[25] Given the broad coverage, we believe that the intra-
peritoneal use of ceftriaxone will lead to better treatment of complex appendicitis and potentially 
decreased incidence of intra-abdominal abscesses. This aligns with typical treatment strategies for 
peritonitis associated with PD catheters, which have been successful.[22, 26, 28] Second or third 
generation cephalosporins are the standard of care antibiotics used pre-operatively prior to an 
appendectomy. At our institution pre-operative intravenous (IV) ceftriaxone (50mg/kg/day, 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 10 of 25 
 
maximum 2g daily) and metronidazole (30mg/kg/day) therapy is used as pre-operative antibiotic 
treatment prior to pediatric appendectomy. [29] Intravenous ceftriaxone (50mg/kg/day, maximum 2g 
daily) and metronidazole(30mg/kg/day) is given post-operatively following the diagnosis of 
complicated appendicitis for a minimum of 48 hours following surgery. The maximum daily dosage 
of intravenous ceftriaxone administered during the conduct of the study will be 2g. We anticipate 
that the intra-peritoneal instillation of ceftriaxone will decrease the length of stay and decrease the 
post-operative development of deep organ space surgical site infection in patients with complicated 
appendicitis due to the longer contact with the inflamed area of the RLQ following removal of the 
nidus of infection, or the appendix. A small volume of instilled ceftriaxone (~10ml solution total) 
will be used so as not to instill a significant amount of additional fluid into the peritoneal cavity.  
The idea of surgical source control paired with direct antibiotic instillation and application to 
the area of infection is an innovative approach to the traditional treatment scheme of complicated 
appendicitis which could be instrumental in decreasing post-operative complications. Antibiotic 
instillation into the peritoneal cavity after appendectomy gives maximal contact time between the 
antibiotic and the bacteria in question, and leads to elevated local antibiotic concentration. To our 
knowledge, no study has ever sought to use antibiotics as a topical, retained solution in an infected 
peritoneum due to complicated appendicitis. We believe that by applying the antibiotics directly to 
site of highest bacterial presence and allowing the medication to remain in contact with this field, 
that the overall response will be better bacterial control and decreased rates of intra-abdominal 
abscess formation and complications. This is a new concept and has not yet been reported in 
pediatric patients with complicated appendicitis. The long-term goal of the study is to compare 
incidence of postoperative deep organ space infection following our standard of care (aspiration of 
intra-peritoneal infected fluid only) compared with aspiration of intra-peritoneal infected fluid 
followed by antibiotic instillation of ceftriaxone. This pilot study will evaluate the feasibility of this 
novel approach and will yield the necessary preliminary data for a larger study to evaluate the 
effectiveness of this treatment scheme.  
 
2.1 Benefit / Risk Assessment  
Appendicitis is one of the most common surgical diagnoses in the pediatric population and 
the most common surgical emergency in children.[1, 2] In complex appendicitis, the sequelae have 
progressed beyond the confines of the organ, and have led to purulent fluid in the intra-abdominal 
space, spillage of intestinal contents, or gross perforation of the appendix. Complicated appendicitis 
occurs in up to 20% of cases and is associated with a much higher morbidity and mortality. [5] 
Previous studies have shown that local treatment of peritonitis associated with PD catheters with 
intra-peritoneal antibiotics has had significant improvement of outcomes.[22, 23, 26, 28] The intra-
peritoneal route is preferable as compared to oral and intravenous antibiotic administration due to 
elevated local levels of the antibiotic above the minimum inhibitory concentration while avoiding 
venipuncture and systemic side effects.[25, 26] There is minimal risk associated with involvement in 
this study given that we will be screening for any history of allergies to penicillin or cephalosporins, 
and excluding these patients. Ceftriaxone is commercially available, has a low risk profile, and is 
generally well tolerated with minimal side effects.  
 
Our treatment period will include a one-time intra-operative dose of intra-peritoneal 
ceftriaxone. Typical dosing strategies for intra-peritoneal ceftriaxone administration occur on a daily 
basis, so our treatment period will also include the 24 hours following intra-peritoneal administration 
of ceftriaxone. All patients diagnosed with acute complicated appendicitis intra-operatively, and 
entered into our study, will also receive a minimum 48 hours of intravenous antibiotics as an 
inpatient, allowing for continued observation.  We will be treating pediatric patients who are intra-


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 11 of 25 
 
operatively diagnosed with complex appendicitis, as defined by any of the following: visible hole in 
the appendix, extra-luminal fecalith, diffuse fibropurulent exudate outside the RLQ/pelvis, or 
intraperitoneal abscess. All patients will have been admitted to Johns Hopkins All Children’s 
Hospital with a diagnosis of acute appendicitis prior to surgical intervention. Patients will then be 
randomized once diagnosed with complex appendicitis intra-operatively. Patients with allergies to 
penicillin or cephalosporins will be excluded pre-operatively, as well as patients who do not meet the 
weight requirement, are pregnant, have a history of neurological conditions such as encephalopathy, 
seizures, myoclonus and non-convulsive status epilepticus, have a known inability to complete a 
30day postoperative follow up, are being treated non-operatively, and those who have been intra-
operatively diagnosed with simple appendicitis.  
3 
DRUG INFORMATION   
Ceftriaxone is a sterile, semisynthetic, broad-spectrum cephalosporin antibiotic for intravenous, 
intramuscular, or intra-peritoneal administration.  
 
 Ceftriaxone sodium is (6R,7R)-7-[2-(2Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-[[(1,2,5,6-tetrahydro-
2-methyl-5,6-dioxo-astriazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7
2-
(Z)(O-methyloxime), disodium salt, sesquaterhydrate. The chemical formula of ceftriaxone sodium is 
C18H16N8Na2O7S3•3.5H2O.  
Ceftriaxone is a white powder, which is soluble in water. In this study ceftriaxone crystalline powder 
will be dissolved in 0.9% sodium chloride solution prior to intra-peritoneal instillation.  
 
1g of ceftriaxone will dissolve in 9ml of 0.9% of sodium chloride solution, and when fully 
withdrawn should result in a total volume of just about 10ml (9.8ml) for intra-peritoneal instillation.  
 
4 
 STUDY DESIGN 
This is a Prospective Randomized Open with Blinding of Endpoint (PROBE) pilot phase 2 
study to evaluate the feasibility and safety of the use of antibiotic instillation in the treatment of 
complex acute appendicitis. All children equal to or greater than 20kg diagnosed with acute 
appendicitis and undergoing urgent appendectomy will be approached for enrollment for this study. 
As there is poor pre-operative diagnostic accuracy for simple versus complex appendicitis, all 
eligible patients presenting with acute appendicitis and their families will be approached for consent. 
Intra-operative assessment will diagnose complex appendicitis. Complex appendicitis will be 
defined as presence of any of the following: visible hole in the appendix, extra-luminal fecalith, 
diffuse fibropurulent exudate outside the right lower quadrant (RLQ)/pelvis, or intraperitoneal 
abscess. Patients will be excluded if they undergo non-operative management of appendicitis, do not 
undergo appendectomy at the time of operation, weigh less than 20kg, are pregnant, are unable to 
complete a 30day postoperative follow up, have impaired renal function (CrCl <15mL/min), have a 
history of neurological conditions (such as encephalopathy, seizures, myoclonus, and non-
convulsive status epilepticus), or are allergic to penicillin or cephalosporins that prohibit the use of 
the antibiotic intra-peritoneal instillation. Patients with a history of anaphylactic reactions to 
penicillin or cephalosporins will be excluded from this study. Patients with a penicillin allergy who 
have previously received IV cephalosporins without allergic reaction will be considered for inclusion 
in this study.   


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 12 of 25 
 
Study participants will be randomized in a 1:1 ratio using permuted blocks of 4 and 6 using a 
computer-generated randomization scheme. The treatment category assignments will be placed in 
consecutive numbered envelopes concealed from study staff until randomization. In the operating 
room, once the patient is diagnosed with complicated appendicitis, then the next sequential envelope 
will be opened and the patient will be assigned to that treatment arm. The surgeon and team 
administering the treatment will not be blinded; however, patients, their families, and hospital 
caregivers outside of the operating room will be blinded to the treatment. Post-operative protocols 
will be the same for both groups and includes continuation of intravenous antibiotics (Study Schema, 
and Fig 1). Once complex appendicitis is diagnosed, and a successful appendectomy occurs, then the 
patient will be transitioned to intravenous ceftriaxone (50mg/kg/day, maximum 2g daily) and 
metronidazole (30mg/kg/day) post-operatively. Both study groups will receive a minimum 
additional 48 hours of intravenous ceftriaxone and metronidazole, as per our weight based current 
standard of care. Patient status and post-operative recovery back to baseline will dictate discharge or 
continued hospitalization. Pending their clinical course, patients will be either transitioned to broad-
spectrum oral antibiotics or continued on intravenous ceftriaxone and metronidazole until their 
discharge from the hospital. Our standardized discharge criteria includes: temperature less than 
38.5ºC for the previous 24 hours, improved abdominal pain without the use of narcotics, and 
tolerance of enteral intake. Once these criteria have been met, and at the surgeon’s discretion, the 
patient will be discharged home with routine follow-up (either a clinic visit, telemedicine visit, or a 
phone call) within 30 days after surgery.  
If the patient remains hospitalized on post-operative day 7 (plus or minus 1 day) related to 
postoperative care of complicated appendicitis, and does not meet discharge criteria as listed, then 
they will undergo subsequent imaging studies (abdominal ultrasound or CT abdomen-pelvis) to 
evaluate for intra-abdominal abscess or phlegmon. If patients are found to have an abscess or 
phlegmon, they will continue to receive ongoing antibiotic treatment with or without percutaneous 
aspiration and/or drainage at the discretion of the surgeon and interventional radiologist.  
Patients will undergo telephone, telemedicine visit, or in-person clinic follow-up within 30-
days of their discharge following their appendectomy. If patients present with symptoms at these 
checks or independently present to an emergency department, they will undergo routine evaluation 
and imaging as clinically indicated. Other parameters that will be tracked include development of 
superficial or deep surgical site infection, inpatient pain scores, inpatient pain medication use, and 
post-operative length of stay.  
An independent clinical endpoint committee will be formed to evaluate for study related 
complications and endpoints.  For consistency and future ease of a prospective multicenter trial, 
definitions of intraoperative findings of complicated appendicitis, postoperative percutaneous 
drainage or aspiration of intraperitoneal fluid collection, surgical site infection, postoperative sepsis, 
readmission and/or reoperation will be reported according to the National Surgical Quality 
Improvement Program Pediatric Operations Manual, January 2022 edition. [31]  
We will evaluate patient retention and recruitment along with the process of instilling 
antibiotic solution into the intra-peritoneal space in this feasibility study. We will primarily focus on 
recruitment, enrollment, and retention rates in this pilot study. We will also evaluate patient 
outcomes associated with intra-peritoneal instillation of antibiotics to determine not only post-
operative complication rates, but also length of stay, pain scores, pain medication use, superficial 
surgical site infections, and adverse events related to the antibiotic instillation. Patients and their 
families will be blinded to their randomized treatment groups, and will be followed for 30 days 
following appendectomy. 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
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Page 13 of 25 
 
4.1 
Number of Participants 
Thirty-six patients will be enrolled. We will screen approximately 400 patients within the 
eighteen-month period.  
4.2 
Number of Study Centers 
This will be a single-center trial. Johns Hopkins All Children’s Hospital will be the only 
participating hospital in this study.  
4.3 
Study Duration  
We will begin screening patients after IRB approval of our pilot study. We will continue 
screening and inclusion in the trial until enrollment is met. We suspect this will take 
approximately eighteen months. The duration of participation will be approximately 30-days 
from the time of appendectomy. We will continue our pilot study until we have enrolled a total 
of 36 patients.  
5 
ELIGIBILITY CRITERIA 
 
All children weighing equal to or greater than 20kg admitted to our institution with a diagnosis of 
acute appendicitis and who undergo urgent appendectomy will be eligible for this study. Patient and 
guardians will be approached with information about the study regardless of pre-operative 
categorization of appendicitis, suspected simple or suspected complex. The patient and family will 
be blinded as to which treatment arm they will receive.  
5.1 
Inclusion Criteria 
5.1.1 Patient diagnosed with acute appendicitis and are scheduled to undergo urgent 
appendectomy 
5.1.2 Patient is between 3-18 years of age at time of appendectomy 
5.1.3 Patient has intraoperative findings of complex appendicitis defined by: visible hole in 
the appendix, extra-luminal fecalith, diffuse fibropurulent exudate outside the 
RLQ/pelvis, or intraperitoneal abscess 
 
5.1.4 Patient weighs equal to or greater than 20kg at time of surgery 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 14 of 25 
 
5.2 
Exclusion Criteria 
5.2.1 Patient is pregnant 
5.2.2 Patient has a penicillin or cephalosporin allergy that is severe or anaphylactic in 
nature, prohibiting the use of these antibiotics 
5.2.3 Patient has simple appendicitis 
5.2.4 Patient who undergoes appendectomy following failed or planned medical 
management of appendicitis 
5.2.5 Patient has impaired renal function (CrCl <15mL/min) 
 
5.2.6 Patient has history of neurological conditions such as encephalopathy, seizures, 
myoclonus and non-convulsive status epilepticus 
 
5.2.7 Patient has a known inability to complete a 30day postoperative follow up 
 
6 
ENROLLMENT GUIDELINES 
 
Participants must meet all of the eligibility requirements listed in Section 5 prior to signing the IRB-
approved informed consent form.   
 
 
6.1 
Screen Failures 
Screen failures are defined as participants who consent to participate in the research but who are 
not subsequently randomized. Individuals who do not meet the criteria for participation in this 
study (screen fail) may not be re-screened.   
7 
ANTIBIOTIC INSTILLATION INTERVENTION PLAN 
7.1 
Intervention Schedule 
 
All patients equal to or greater than 20kg presenting to Johns Hopkins All Children’s Hospital 
with a diagnosis of acute appendicitis and are scheduled to undergo urgent appendectomy will be 
approached for participation in this study. Intra-operatively their eligibility to participate in the 
study will be determined. If complex appendicitis is found intra-operatively then the patient will 
be randomized into the control group (standard of care arm with intra-peritoneal fluid aspiration 
only), or the study group (intra-peritoneal fluid aspiration and antibiotic solution instillation). 
Antibiotic instillation will be introduced into the RLQ/pelvis after the appendectomy is completed 
and all intra-peritoneal fluid is aspirated. Ceftriaxone solution will be used depending on 
availability and pharmacy stock for use at Johns Hopkins All Children’s Hospital. The ceftriaxone 
powder (1g) will be dissolved in 9ml of sterile normal saline. The entire contents of reconstituted 
powder will be fully withdrawn for a total instillation volume of 10ml. This fluid will then be 
instilled and left to dwell in the area of the peritoneal cavity where the appendix was removed.  


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 15 of 25 
 
 
Intervention 
 
Standard of Care (Control group)/ARM A 
Intra-operative aspiration of intra-peritoneal fluid after successful appendectomy. 
 
Standard of Care and Antibiotic instillation (Study group)/ARM B 
Intra-operative aspiration of intra-peritoneal fluid after successful appendectomy and subsequent 
instillation of 10ml of intra-peritoneal ceftriaxone (1g)  
7.2 
Third Generation Cephalosporin Intra-peritoneal Instillation Treatment  
7.2.1 How Supplied, Stored, Packaged and Labeled 
 
Ceftriaxone powder is stored in glass bottles in the OR Pyxis at room temperature 
with printed labels, noting dose and amount. 
7.2.2 Preparation and Administration 
 
 
The sterile ceftriaxone powder (1g) will be mixed with 9ml of sterile 0.9% normal 
saline. The entire contents of reconstituted powder will be fully withdrawn, for a total volume 
of 10mL. This solution will then be sterilely transferred to the surgical field and administered 
into the intra-peritoneal space under direct visualization prior to closure of the fascia.  
 
 
7.2.3 Accountability and Compliance 
 
Pending inclusion and randomization into the trial, the patient will be randomized 
into one of the two treatment arms. The patient will either receive the standard of care 
treatment arm, or the standard of care treatment arm with intra-peritoneal instillation of 
ceftriaxone. The amount of ceftriaxone used will be recorded in the patient’s record in the 
EMR (Epic) by the circulating nurse in the operating room. The dose of ceftriaxone, and 
route will be verbally communicated to the operating surgeon who will agree with said 
treatment and document within their operative note.  
7.3 
Prohibited Concomitant Medications 
 
Not applicable. 
7.4 
Duration of Therapy / Intervention 
 
Participants must be withdrawn from the study treatment for the following reasons:  
•    Participant withdraws consent from the study treatment and/or study procedures.  A 
participant must be removed from the trial at his/her own request or at the request of his/her 
legally acceptable representative.  At any time during the trial and without giving reasons, 
a participant may decline to participate further.  The participant will not suffer any 
disadvantage as a result. 
•    Participant is lost to follow-up. 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
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•    Death. 
 
Participants may be withdrawn from the study for the following reasons:  
• The participant is non-compliant with study drug, trial procedures, or both. 
• If, in the investigator's opinion, continuation of the trial would be harmful to the subject's 
well-being. 
• Development of a concurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
7.5 
Lost to Follow Up 
 
A participant will be considered lost to follow up if s/he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  Before a participant is deemed 
lost to follow up, the investigator or designee must make every effort to regain contact with the 
participant.  Where possible, three (3) telephone calls and a certified letter to the participant’s last 
known mailing address per their medical record.  These contact attempts will be documented in 
the research record.   
8 
TOXICITIES AND DOSE MODIFICATION 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) version 
5.0 for adverse events and serious adverse event reporting.  A copy of the CTCAE Version 5.0 can 
be downloaded: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Refer
ence_8.5x11.pdf 
8.1 
Adverse Events (AEs) 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study intervention even if the event is not considered to be 
related to study intervention. For the purposes of this study, the terms toxicity and adverse event 
are used interchangeably. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study intervention. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
 
AEs will be collected from the date of the operative intervention (with or without instillation of 
antibiotics) to 30 days after the operative date. Given the one-time study intervention and dosing 
timeline, any adverse effects should be seen well within the first 48 hours after administration. 
However, we will continue to review, document, and intervene on any adverse events that occur 
within the first 30 days following surgery. 
 
Information about adverse events, whether volunteered by the participant, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected, recorded, and followed as appropriate. 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
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Page 17 of 25 
 
The occurrence of adverse events should be sought by non-directive questioning of the 
participant at each visit or phone contact during the study. Adverse events also may be detected 
when they are volunteered by the participant during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse event should 
be evaluated to determine at a minimum: 
1. The severity grade based on CTCAE v.5 (grade 1-5) 
2. Its relationship to the study intervention (definite, probable, possible, unlikely, unrelated)  
3. Its duration (start and end dates or if continuing at final exam) 
4. Whether it constitutes an SAE 
 
All adverse events are expected to be treated appropriately. Once an adverse event is detected, it 
will be followed until its resolution. 
 
Information about common side effects already known about the commercial drug (third 
generation cephalosporin) is described in the Drug Information (section 3) and the FDA-
approved product labels. This information is included in the participant informed consent and/or 
assent and will be discussed with the participant during the study, as needed. 
 
All adverse events are recorded in the participant research chart. 
8.2 
Serious Adverse Events (SAEs) 
Information about all serious adverse events is collected and recorded. A serious adverse 
event is one which meets any of the following criteria: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o Routine treatment or monitoring of the studied indication, (such as ongoing pain, 
fever, constipation, bowel obstruction, surgical site infections, or other infections) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
o Is medically significant (i.e. defined as an event that jeopardizes the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above) 
 
Events that fall within the definitions listed above must be reported as SAEs, irrespective of 
whether they are judged to be related to treatment or not. If an event is not an AE per the 
definition in section 9.1, then it cannot be an SAE, even if serious conditions are met (e.g. 
hospitalization, death due to progression of disease etc.).  However, such events may meet JHM 
IRB reportable definitions as a UPIRSO (see section 9.3). Toxicities unrelated to treatment that 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 18 of 25 
 
do NOT fall within the definitions above, must simply be documented as AEs in the participant 
research chart.  
 
Collection of serious adverse events will begin after the patient is randomized into the study 
intra-operatively and will end 48 hours after administration of the intra-peritoneal antibiotics. It 
is very unlikely that any serious adverse event will occur given that this study intervention uses a 
commercially available antibiotic that is routinely administered both parenterally and locally. 
Adverse events due to intra-peritoneal antibiotic instillation may be difficult to distinguish given 
that similar antibiotics will be given intravenously.  
8.3 
Unanticipated Problems Involving Risks to Participants or Others (UPIRPO) 
JHM IRB defines UPIRPOs as events or information that is unexpected in terms of nature, 
severity, or frequency given the research procedures described in the protocol, the informed 
consent form, and the characteristics of the participant populations AND indicates that 
participants or others are at greater risk of harm (physical, psychological, economic, or social) 
than previously known or recognized.  Events meeting the JHM IRB requirements for UPIRPOs 
(https://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/organization_
policies/103_6b.html) are reported promptly to JHM IRB.   
 
8.4 
Reporting Requirements 
SAEs will be reported to the overall PI, and the IRB. 
 
SAE and UPIRSO Reporting to the IRB: 
• Events meeting the JHM IRB requirements for UPIRSOs will be reported promptly to the 
IRB.   
 
The MedWatch report will be submitted to the FDA through the voluntary reporting method by 
the PI. 
A MedWatch 3500A form must be completed and submitted to the FDA as soon as possible, but 
no later than 10 days of first knowledge or notification of event (5 days for fatal or life-threatening 
event). 
 
MedWatch 3500A form can be found at:  
https://www.fda.gov/safety/medical-product-safety-information/medwatch-forms-fda-safety-
reporting 
8.5 
Supportive Care 
8.5.1 All supportive measures consistent with optimal patient care will be given throughout 
the study. 
 
9 
STUDY CALENDAR 
 
MONTHLY Calendar 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 19 of 25 
 
Test / Procedure 
Pre-
study1 
Surger
y 
POD
1 
POD
3 
POD
4 
POD
5 
POD
6 
POD
7 
POD
14 
POD
<30 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Vital signs2 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination2 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
CBC with diff2 
X 
 
 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Urine pregnancy 
test4 
X 
 
 
 
 
 
 
 
 
 
Pain Score2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
and record of 
treatment group 
 
X 
 
 
 
 
 
 
 
 
Telephone or In-
person Follow up 
 
 
 
 
 
 
 
 
X 
X 
Pre-operative 
imaging (US or 
CT scan) 
X 
 
 
 
 
 
 
 
 
 
Post-operative 
imaging (US or 
CT Scan)5 
 
 
 
 
 
 
 
X3 
 
 
1 All Pre-study/Screening procedures should be completed within 24 hours of study enrollment  
2 To occur if the patient is still admitted, or seen in follow up 
3 To occur at the discretion of the surgeon when clinically warranted  
4 Required for any female greater than 10 years old prior to receiving general anesthesia 
5 If patient continues to have an elevated WBC, pain on exam, a fever within the last 24 hours or is 
unable to tolerate a diet.   
10 STUDY PROCEDURES  
Screening: 
Informed Consent 
Pre-op Physical exam: Height, weight, abdominal exam  
Review of medical history/baseline symptoms including pain score 
Pre-op Vitals: heart rate, blood pressure, respiratory rate, pulse oximetry, temperature 
Pre-op pain score 
Pre-op Labs: CBC w/diff, pregnancy test if warranted 
Pre-op imaging: Ultrasound or CT scan 
 
Surgery: 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 20 of 25 
 
Successful appendectomy will be defined as removal of the appendix and appropriate closure of the 
cecum.  
After successful appendectomy and identification of complex appendicitis, the patient will be 
randomized into the standard of care arm, or the standard of care with antibiotic instillation arm.  
 
Post-operative monitoring: 
Post-operative inpatient Physical exam: abdominal exam  
Post-operative inpatient Vitals: heart rate, blood pressure, respiratory rate, pulse oximetry, 
temperature 
Post-operative pain score 
Post-operative Inpatient Labs: CBC w/diff if the patient remains hospitalized and is deemed 
clinically necessary by the surgeon 
Post-operative imaging: will occur on POD7 (+/- 1 day) if the patient is still hospitalized and 
continues to have severe or recurrent abdominal pain, is unable to tolerate a diet, was febrile within 
the last 24 hours and if clinically warranted has a recent CBC with an elevated WBC.  
 
Follow-up appointment: 
Outpatient follow up Physical exam: abdominal exam  
Outpatient follow up Vitals: heart rate, blood pressure, respiratory rate, pulse oximetry, temperature 
Pain score 
 
11 CRITERIA FOR EVALUATION AND ENDPOINT 
 
11.1 Efficacy 
Our study is looking to investigate the feasibility of using intra-abdominal antibiotic instillation 
following a successful appendectomy for acute complex appendicitis. Within this study we will 
investigate the incidence of deep organ space surgical site infection after a one-time dose of 
intra-peritoneal antibiotic instillation following a successful appendectomy for acute complex 
appendicitis. We will review length of stay, inpatient pain medication use, inpatient pain scores, 
and superficial surgical site infection of the two groups. We will also review complications and 
any need for further intervention. Each patient will be followed for a total of 30 days post-
operatively.  
 
12 STATISTICAL CONSIDERATIONS 
 
A JHACH database manager will create a REDCap database for the study on the password-
protected JHACH secure network. A Pediatric Surgery Research Fellow will enter data, and the 
Principal Investigator will check the initial data on six participants for accuracy and completeness 
and spot-check the data entry independently at least once a month.  
  
All data will be checked for completeness and consistency at the end of the study. Tabular 
and graphical methods will be used to explore the distribution of the variables. Baseline 
demographic and clinical characteristics will be summarized using descriptive statistics for 
continuous (mean, standard deviation, median, range) and categorical variables (counts, 
percentages). Baseline differences between the groups will be evaluated using independent t-test or 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 21 of 25 
 
Mann Whitney U test for continuous variables as appropriate, and Chi-squared or Fisher’s exact test 
for categorical variables as appropriate. All statistical analyses will be performed with SAS v 9.4 or 
a newer version. 
 
 
Analysis for Aim 1. 
The primary aim of this study is to determine the feasibility and safety of the use of antibiotic 
solution instillation following intraoperative diagnosis of complex appendicitis. We will 
determine feasibility by the percentage of eligible participants who (1) agree to participate, 
and (2) complete all intervention sessions and measurement time points. Safety will be 
determined by adverse events associated with the use of intra-peritoneal antibiotic instillation 
for the treatment of peritonitis caused by complex appendicitis. For feasibility, we will report 
the proportions with corresponding 95% confidence intervals for eligibility, recruitment, 
enrollment, withdrawals and drop outs, and study completion. We will also collect 
information on barriers and issues of implementation. The study will be deemed feasible if 
>50% of potential participants agree to participate and at least 75% of them complete all 
measurement time points. These benchmarks are based on a previous similar study 
completed in this population. [29]. For safety we will report the incidence of adverse effect 
with the corresponding 95% confidence interval. 
 
  
Analyses for secondary aims 
We will perform an exploratory efficacy analysis to compare the antibiotic solution instillation group 
and the control participants on outcome measures. We will initially compare categorical outcomes 
using Chi-squared or Fisher’s exact test as appropriate and independent t-test or Mann Whitney U 
test for continuous variables as appropriate. We will attempt to use logistic or linear regression as 
appropriate for the outcome measure to adjust for baseline characteristics that differ between the 
groups. The main analysis for this aim will be a modified intention-to-treat for the primary analysis. 
For this analysis, patients will be compared in the two arms based on how they were randomized and 
it will include all patients that were randomized and received surgery. We will also perform 
supportive per protocol and as treated analyses. Based on historical data from our institution, we 
anticipate that <1% of patients who are initially randomized to one arm may switch to the other arm 
during surgery and approximately <1% may not complete the surgery. These patients will be 
considered as a protocol violation and will be excluded from the per protocol analysis. The as treated 
analysis will group the patients according to the type of surgery they actually received and exclude 
those that did not complete or receive surgery. The analyses for this aim will be exploratory, as the 
study is not powered to detect clinically important differences between groups using these analyses. 
However, the findings from these analyses will be used to guide the design of a future larger study 
that will include appropriate sample size estimations or power analyses. 
 
Attrition and Missing Data:  
We will make every effort to reduce attrition. Missing data will be characterized and 
examined for non-randomness. Missing data will not be imputed.  
 
 
Sample size justification:  


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 22 of 25 
 
The primary aim of this study is to assess feasibility of the proposed intervention to inform a 
future larger randomized controlled trial. Therefore, the sample size is not based on a power 
analysis. A sample size of 36 participants (18 intervention and 18 control) is appropriate to provide 
feasibility data that will help refine our intervention and measurements for a future larger study.[30] 
This sample size will allow us to estimate a conservative participation of 70% with a confidence 
interval of 53-87%. In a similar study conducted by the PI previously, 85% of recruited families 
consented to randomization and >93% of those families completed all study assessments.  
Based on current estimates in our institution, we anticipate 350 appendectomies to be 
performed each year. Assuming the average documented 20% perforation rate, we anticipate 70 
appendectomies for complicated appendicitis each year. Therefore, we will have an eligible pool of 
70 patients with intra-operatively diagnosed complicated appendicitis. [29]   
 
Study Monitoring and stopping rules: 
 
All patients will be monitored in the post-operative period, particularly the first 48 hours 
following surgery. Given the study involves a single dose of intra-peritoneal antibiotic instillation any 
drug side effects will likely occur within the first 12 hours of treatment. At any time in the study, if a 
patient suffers an adverse event secondary to intra-peritoneal antibiotic instillation, all study activity 
will be suspended until a full investigation is completed. The study will only be reinstated after 
consultation with the Johns Hopkins All Children’s Hospital IRB. Patients with severe allergies to 
cephalosporins or penicillin will be excluded from the study.   
 
13 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each participant that 
provide a record of the data generated according to the protocol.  CRF’s should be created prior to 
the study being initiated and updated (if applicable) when amendments to the protocol are IRB 
approved.  Data capture should be restricted to endpoints and relevant participant information 
required for planned manuscripts.  These forms will be completed on an on-going basis during the 
study.  The medical records will be source of verification of the data.  During the study, the CRFs 
may be monitored for completeness, accuracy, legibility and attention to detail by a member of the 
Regulatory Affairs / Quality Assurance department. The CRFs are completed by the Investigator or a 
member of the study team as listed on the Delegation of Authority log. The Investigator agrees to 
allow Regulatory Affairs / Quality Assurance personnel access to participants’ source documents, 
clinical supplies dispensing and storage area, and study documentation for the above-mentioned 
purpose.  
 
14 ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 Informed consent  
Informed consent is obtained from all research participants and/or the legal guardian prior to 
performing any study procedures using the most recent IRB approved version.  
14.2 Institutional Review 
Research is approved by the Johns Hopkins Medicine Institutional Review Board, or other IRB 
of Record, as appropriate.   


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
Page 23 of 25 
 
14.3 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the period for which 
the IRB approval has already been given are not initiated without submission of an amendment 
for IRB review and approval.    
 
These requirements for approval in no way prevent any immediate action from being taken 
by the investigator in the interests of preserving the safety of all participants included in the 
trial.  
14.4 Protocol Deviations 
A protocol deviation is any departure from the defined procedures and treatment plans as 
outlined in the protocol version submitted and previously approved by the IRB. Protocol 
deviations have the potential to place participants at risk and can also undermine the scientific 
integrity of the study thus jeopardizing the justification for the research.   
 
The JHM IRB requires the prompt reporting of protocol deviations which are: 
• 
Emergency deviations (when immediate deviations are required to protect the life or 
physical well-being of a participant) 
• 
Major (representing a major change in the approved protocol), non-emergent 
deviation occurring without prior IRB approval  
 
Minor or administration deviations, which do not affect the scientific soundness of the 
research plan or the rights, safety, or welfare of human participants, are reported to the JHM 
IRB at the time of continuing review.   
14.5 FDA Annual Reporting  
 
This study is being conducted under an IND submission. Therefore, annual reporting of the 
study’s progress is required by and will be submitted to the FDA.   
 
14.6 Clinical Trials Data Bank  
 
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the PI.  
 
14.7 Record Keeping 
As per 21 CFR 312.57, the study investigator records will be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or the 
application is not approved, until 2 years after the investigation is discontinued and the FDA is 
notified. 
 
 
 
 


Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
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Page 24 of 25 
 
15 BIBLIOGRAPHY  
1. 
Grabowski, J.M.D. and S.M.D. Lee, Appendicitis. 2018. 
2. 
Stringer, M.D., Acute appendicitis. J Paediatr Child Health, 2017. 53(11): p. 1071-1076. 
3. 
Dickinson, C.M., N.A. Coppersmith, and F.I. Luks, Early Predictors of Abscess 
Development after Perforated Pediatric Appendicitis. Surg Infect (Larchmt), 2017. 18(8): p. 
886-889. 
4. 
Rogers, A.P., et al., A call for a standardized definition of perforated appendicitis. J Pediatr 
Surg, 2017. 52(1): p. 89-92. 
5. 
Anderson, K.T., et al., Povidone-iodine Irrigation for Pediatric Perforated Appendicitis May 
Be Protective: A Bayesian Pilot Randomized Controlled Trial. Ann Surg, 2019. 
6. 
St Peter, S.D., et al., An evidence-based definition for perforated appendicitis derived from a 
prospective randomized trial, in J Pediatr Surg. 2008: United States. p. 2242-5. 
7. 
Henry, M.C., et al., Risk factors for the development of abdominal abscess following 
operation for perforated appendicitis in children: a multicenter case-control study, in Arch 
Surg. 2007: United States. p. 236-41; discussion 241. 
8. 
Kleif, J., et al., Enteral Antibiotics are Non-inferior to Intravenous Antibiotics After 
Complicated Appendicitis in Adults: A Retrospective Multicentre Non-inferiority Study. 
World J Surg, 2017. 41(11): p. 2706-2714. 
9. 
Sun, F., et al., Copious Irrigation Versus Suction Alone During Laparoscopic Appendectomy 
for Complicated Appendicitis in Adults. J Invest Surg, 2018. 31(4): p. 342-346. 
10. 
Escolino, M., et al., Infectious Complications After Laparoscopic Appendectomy in Pediatric 
Patients with Perforated Appendicitis: Is There a Difference in the Outcome Using Irrigation 
and Suction Versus Suction Only? Results of a Multicentric International Retrospective 
Study. J Laparoendosc Adv Surg Tech A, 2018. 28(10): p. 1266-1270. 
11. 
St Peter, S.D., et al., Irrigation versus suction alone during laparoscopic appendectomy for 
perforated appendicitis: a prospective randomized trial. Ann Surg, 2012. 256(4): p. 581-5. 
12. 
Snow, H.A., et al., Irrigation versus suction alone during laparoscopic appendectomy; A 
randomized controlled equivalence trial. Int J Surg, 2016. 28: p. 91-6. 
13. 
Moore, C.B., et al., Does use of intraoperative irrigation with open or laparoscopic 
appendectomy reduce post-operative intra-abdominal abscess? Am Surg, 2011. 77(1): p. 78-
80. 
14. 
Hajibandeh, S., et al., Irrigation Versus Suction Alone in Laparoscopic Appendectomy: Is 
Dilution the Solution to Pollution? A Systematic Review and Meta-Analysis. Surg Innov, 
2018. 25(2): p. 174-182. 
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Date: September 27, 2023 
Principal Investigator: Nicole M. Chandler, MD 
Application Number: IRB00323208 
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