Probiotics and Antibiotic Associated Diarrhea in Pediatric Complicated Appendicitis: Prospective Controlled-Comparison Trial
Phase: NA
Conditions: Appendicitis, Appendicitis; Perforation
Sponsor: Children's Health

Version 2.0 
Page 1 of 6 
December 15, 2020 
 
 
 
 
 
 
 
 
 
 
Title: Probiotics and antibiotic associated diarrhea in pediatric complicated appendicitis: Prospective 
Controlled-Comparison Trial 
 
 
 
NCT NCT04529980 
 
 
 
 
December 15, 2020 

Version 2.0 
Page 2 of 6 
December 15, 2020 
 
The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol Template (for Investigator Initiated Studies) 
 
 
Title: Probiotics and antibiotic associated diarrhea in pediatric complicated appendicitis: Prospective 
Controlled-Comparison Trial 
 
Principal Investigators: 
Mayra Garcia, DNP, APRN, PCNS-BC 
Hayden Dutton, MSN, RN, CPN 
 
Faculty Sponsor: Adam Alder, MD 
 
Purpose: To determine the effectiveness of the use of probiotics in patients with a diagnosis of 
complicated appendicitis on antibiotic associated diarrhea (AAD). 
 
Background: 
Appendicitis is the most common urgent surgical procedure performed on children. Approximately 
one third of the population end up having complicated appendicitis with evidence of peritoneal 
contamination and infection or abscess requiring the use of IV antibiotics and prolonged hospital stay. 
Antibiotic Associated Diarrhea (AAD) is a common complication seen in both outpatient and inpatient 
settings in approximately a third of all patients treated with antibiotics (Mantegazza, et al., 2018). In 
particular, pediatric patients experience ADD 11-62% of the time and can up upwards to 80% in 
hospitalized toddlers (Mantegazza, et al., 2018). Current literature defines AAD as three or more 
liquid stools per day. The causes of AAD are often related to the use of multiple antibiotics, prolonged 
hospital stay and gastrointestinal surgery. Antibiotics often disturb the normal enteric microbiome in 
the gut and allow for an increased growth of pathogens (Hojsak, 2017). AAD can occur as late as six 
to eight weeks after antibiotic exposure. 
 
Probiotics are defined as live microbial organisms that when administered in sufficient amounts, can 
provide a protective benefit to the host (Hojsak, 2017). Use of probiotics in a pediatric population 
exposed to antibiotics and gastrointestinal surgery such as an appendectomy may provide a 
protective effect and prevent ADD (Alper, Zangwill, LaRue & Manheimer, 2017; Hayes & Vargas, 
2016). In a meta-analysis of randomized controlled trials in pediatrics, literature found that treatment 
with Lactobacillus rhamnosus GG (LGG) reduced in risk of ADD from 23% to 9.6% (RR, 0.48; 95% 
CI, 0.26 to 0.89) (Szajewska & Kolodziej, 2015). Studies indicate it is suggested to administer LGG 
simultaneously with the initiation of antibiotic therapy, before the modification of gut microbiota and 
overgrowth of pathogens (Szajewska & Kolodziej, 2015). 
 
Lactobacillus rhanmosus GG(LGG®)(Culturelle) is an over the counter dietary supplement that can 
help to restore the balance in the gut by promoting colonization to support better digestion and 
immune health. As such, this dietary supplement is not reviewed and approved by the FDA. This 
study does not intend to investigate route of administration, dose, patient population, or other factor 
that significantly increases the risk (or decreases the acceptability of the risk) associated with the use 
of the dietary supplement. 
 
At Children’s Medical Center, we see over 1000 cases of appendicitis a year with approximately 1/3 of 
those patients being complicated appendicitis. Our current treatment at Children’s Medical Center for 

Version 2.0 
Page 3 of 6 
December 15, 2020 
 
complicated appendicitis follows two pathways: 1) drainage and deferred appendectomy 
approximately 6 to 8 weeks later or 2) immediate appendectomy. All children are typically admitted to 
the hospital for 3 to 5 days, receive a course of IV antibiotics while in hospital and are discharged with 
oral antibiotics to complete their treatment. There has been an increase in the number of patients 
receiving prescribed probiotics after surgery. 
 
We propose to perform a randomized controlled trial where one group of patients receive probiotic 
therapy and another group of patients does not. 
 
We hypothesize patients given probiotics after a diagnosis of complicated appendicitis with immediate 
appendectomy who receive antibiotic treatment during their inpatient stay will decrease the overall 
length of stay (LOS) by 25% vs the LOS in those patients who do not receive probiotics. 
 
3. Concise Summary of Project: 
Upon IRB approval, patients admitted to the pediatric surgery service with complicated appendicitis 
who undergo an immediate appendectomy will be approached about participation in the study. Once 
written consent has been obtained, patients will be randomized into one of two potential study groups. 
Those randomized to the treatment group will be given probiotic therapy until discharge, while those 
randomized to the placebo group will be given a placebo until discharge. Data will be collected from 
the Electronic Health Record (EHR) at Children’s Medical Center will include MRN, standard 
demographics, length of stay, presence or absence of diarrhea, ambulation/activity level, abdominal 
pain, stool counts, surgical history, medications, emergency department visits and readmission rates. 
Data will be stored in a CMC/UTSW secured RedCap with access only granted to study team 
members. 
 
4. Study Procedures: 
 
Design. Prospective Randomized Controlled Trial 
 
Sample. 
Data will be obtained from the electronic health record (EHR) from a convenience sample of patients 
in a single-center pediatric inpatient surgery unit with a diagnosis of complicated appendicitis that 
undergoes an immediate appendectomy. 
 
Patients will be randomized into two study groups using randomization and utilizing a sealed envelope 
randomization plan. 120 envelopes will be sealed with a standard sized document marked “probiotic 
treatment” and 120 envelopes will be sealed with a standard sized document marked “placebo”. 240 
envelopes will be thoroughly shuffled then labeled sequentially from 1-240 in pen. Envelopes will be 
placed in a plastic container in numerical order ready for use. One group of 120 patients will be given 
probiotic therapy until discharge and the other group of 120 patients will be given a placebo until 
discharge 
 
Methods: 
After the appendectomy, patients who meet the inclusion criteria and none of the exclusion criteria will 
be approached by the study team and offered participation for this study. Patients and families will be 
approached after their surgery on the inpatient floor. A member of the research team will provide 
families information about the study in their preferred language (English/Spanish). A consent will be 
signed and scanned into to the patient’s medical record. 
 
Those who are in agreeance will be consented for the study following all IRB procedures. 
Randomization will be used to allocate patients into treatment and control group. The treatment group 
includes 120 patients who have immediate appendectomy and will receive probiotics. The control 
group includes 120 patients who have an immediate appendectomy and will receive a placebo. 

Version 2.0 
Page 4 of 6 
December 15, 2020 
 
Patient and Family 
approached about 
study. Consent is 
obtained 
Patient is assigned in 
intervention group and 
is given probiotic 
medication until 
discharge. 
Patient is assigned in 
control group. Patient 
is given placebo until 
discharge. 
Patient is randomized 
into control group or 
intervention group 
using sealed envelope 
randomization plan. 
Patients in the treatment group will receive a standard dose of Lactobacillus rhamnosus GG capsule 
twice a day until discharge. The control group will receive a placebo until discharge. If the patient is 
unable to swallow the probiotic capsule or placebo, the capsule can be opened and sprinkled with 
food. Current antibiotic standard of care for complicated appendicitis patients includes: ceftriaxone 
RTA 50mg/kg dose every 24 hours x 7 days and metronidazole RTA 30mg/kg dose every 24 hours x7 
days. In patients with a sensitivity to ceftriaxone, metronidazole RTA 30mg/kg dose every 24 hours x7 
days and ciprofloxacin 10-15 mg/kg every 8 hours x 7 days will be administered. 
Treating medical team and patients/family will be blinded to whether patient is on probiotic or placebo. 
Data will be collected as stated in section titled, “Concise Summary of Project.” 
5. Criteria for Inclusion of Subjects: 
• 
Patients with a post-operative diagnosis of complicated appendicitis who undergo an 
immediate appendectomy. 
• 
Patients between the ages of 4 and 18 years of age. 
 
6. Criteria for Exclusion of Subjects: 
• 
Patients diagnosed with a complicated appendicitis with deferred appendectomy or non- 
perforated appendicitis 
• 
Patients that have a history of being immunosuppressed, on immunosuppression therapy, or 
long-term steroid therapy within the last month. 
• 
Patients that have central line access. 
• 
Patients under 4 years of age. 
• 
Patients that are developmentally delayed and cannot ambulate at baseline. 
• 
Patients with significant past medical history. 
• 
Patients that are in Child Protective Services custody. 
• 
Patients that are incarcerated. 
• 
Patients that are pregnant. 
• 
Patients that speak languages other than English and Spanish. 
 
 
Study Procedures 
 
 
 
 
7. Sources of Research Material: 

Version 2.0 
Page 5 of 6 
December 15, 2020 
 
All participants will be patients under the care of the General Surgery Department. Information from 
the Children’s Medical Center EHR will be reviewed. Data on outcomes such as length of stay, 
presence or absence of diarrhea, ambulation/activity level, abdominal pain, surgical history, 
medications, emergency department visits, readmission rates and stool counts will be extracted from 
medical records. Standard demographic data will also be obtained. 
 
8. Recruitment Methods and Consenting Process: 
After confirmed complicated appendicitis diagnosis, patients and families will be approached by the 
study team to participate in the study. If families agree to participate, written consent will be obtained, 
and the patient will be randomized to a study group. 
 
9. Potential Risks: 
Inadvertent disclosure of personal medical information. Special precautions are mentioned below in 
the paragraph Procedures to Maintain Confidentiality. 
 
There are potential risks for patients taking probiotics. There have been reported accounts of sepsis in 
immunosuppressed patients receiving probiotics. Our study will exclude patients with a history of 
being immunosuppressed, on immunosuppression therapy, or long-term steroid therapy within the last 
month. 
 
There is a potential risk of psychological stress. Some of the questions we will ask may make the 
patient/legal guardians feel uncomfortable. 
 
10. Subject Safety and Data Monitoring: 
All data will be stored on a password protected computer approved by UTSW and CMC. Access to 
study data will be restricted to authorized study personnel only. 
 
All data will be stored on a password protected computer in a RedCap system approved by UTSW 
and CMC. Access to study data will be restricted to authorized study personnel only. 
 
The Principal Investigators and faculty sponsor will review all patient outcomes on a monthly basis. 
All adverse events, expected and unexpected will be reviewed within 24 hours by the study team and 
reported to the DSMB and the IRB as per policy. 
 
11. Procedures to Maintain Confidentiality: 
All patient information and case report forms will be kept in a locked office with limited access. All 
computer files will be password protected, encrypted and stored on a secure server. Access will be 
limited to study team members only. Data will be collected and stored in a secured CMC server in 
RedCap. The case report includes a unique subject number. The data will be collected, analyzed, 
and archived following strict confidentiality guidelines. The Investigator will consider all information, 
results, discoveries, records accumulated, records acquired, or deductions in the course of the study 
as confidential; other than that information to be disclosed by law. 
 
12. Potential Benefits: 
There may be benefit to those patients who receive a probiotic during their course of treatment in a 
reduction of the incidence of AAD. Future patients may benefit if the protocol proven to be effective in 
decreasing the incidence of AAD. 
 
13. Sample size calculation 
Based on the patient population in Children’s Medical Center Dallas, the mean and standard deviation 
of LOS is 114 and 75.6 hours, respectively. The LOS in the probiotic group is expected to be 75% of 
the control group. With 120 patients in each group, we have 83% of power to detect statistically 
significant difference in LOS between the probiotic group and control group. 

Version 2.0 
Page 6 of 6 
December 15, 2020 
 
14. Biostatistics 
Descriptive analyses of the continuous and categorical data were performed using means, confidence 
intervals, proportions and frequencies. Wilcoxon Rank Sum test will be used to compare the LOS, as 
well as the number of diarrheas, between the treatment group and control group. To investigate which 
type of patients benefits the most from the treatment, regression analysis will be used to model log- 
transformed LOS. The independent variable will be treatment type and prognostic factors. The 
statistical analyses were performed with SAS 9.4. 
 
 
References: 
Agamennone, V., Krul, C. A. M., Rijkers, G., & Kort, R. (2018). A practical guide for probiotics applied 
to the case of antibiotic-associated diarrhea in The Netherlands. BMC Gastroenterology, 
18(1):103. https://doi.org/10.1186/s12876-018-0831-x 
 
Alper, B. S., Zangwill, M., LaRue, J., & Manheimer, E. W. (2017). Point of care application of: 
‘Probiotics for the prevention of pediatric antibiotic-associated diarrhea’ (Cochrane review). 
European Journal of Integrative Medicine, 12: 129-130. 
https://doi.org/10.1016/j.eujim.2017.06.001 
 
Hayes, S. R. & Vargas, A. J. (2016). Probiotics for the Prevention of Pediatric Antibiotic-Associated 
Diarrhea. Explore NY, 12(6): 463-466. doi: 10.1016/j.explore.2016.08.015 
 
Hojsak, I. (2017) Probiotics in Children: What Is the Evidence?. Pediatr Gastroenterol Hepatol 
Nutr.;20(3):139-146. https://doi.org/10.5223/pghn.2017.20.3.139 
 
Mantegazza, C., Molinari, P., D’Auria, E., Sonnino, M., Morelli, L., & Zuccotti, G. V. (2018). Probiotics 
and antibiotic-associated diarrhea in children: A review and new evidence on Lactobacillus 
rhamnosus GG during and after antibiotic treatment. Pharmacological Research, 128, 63–72. 
https://doi.org/10.1016/j.phrs.2017.08.001 
 
Szajewska, H., & Kołodziej, M. (2015). Systematic review with meta-analysis: Lactobacillus 
rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. 
Alimentary Pharmacology & Therapeutics, 42(10), 1149–1157. 
https://doi.org/10.1111/apt.13404 
 
Wanke, M. & Szajewska, H. (2014). Probiotics for preventing healthcare-associated diarrhea in 
children: A meta-analysis of randomized controlled trials. Pediatria Polska, 89(1): 8-16. 
https://doi.org/10.1016/j.pepo.2013.12.003