Appendectomy vs. Symptomatic Treatment in Uncomplicated Acute Appendicitis Among Pediatric Patients (APPSYPP)

A Randomized, Controlled Multicenter Feasibility Pilot Trial on Imaging Confirmed Uncomplicated Acute Appendicitis: Appendectomy vs. Symptomatic Treatment in Pediatric Patients (the APPSYPP) Trial Study Protocol

The APPSYPP trial is a randomized national multicenter feasibility superiority pilot study comparing appendectomy with symptomatic treatment in children with imaging-confirmed uncomplicated acute appendicitis. Patients are recruited from all five Finnish university hospitals. Inclusion criteria are: 1) age 7-15 years, 2) imaging-confirmed uncomplicated acute appendicitis (no appendicolith, perforation, abscess, or tumor suspicion), and 3) CRP ≤ 65 mg/l. Patients are randomized to receive emergency appendectomy or symptomatic treatment. In the surgery group, patients undergo laparoscopic appendectomy within 18 hours after randomization. In order to ensure patient safety, symptomatically treated patients are hospitalized for at least 24 hours, and receive intravenous fluids and analgesics according to standard clinical practice. Primary outcome is treatment success at 30 days defined by not fulfilling any of the treatment failure criteria. In the surgery group, treatment failure is defined as normal appendiceal histopathology or any postintervention complication requiring general anesthesia. In the symptomatic treatment group, treatment failure is defined as inability to discharge from hospital without appendectomy within 48 hours after randomization with a finding of histopathologically inflamed appendix, appendectomy during the initial hospital stay due to clinical progression of appendicitis with histopathologically and surgically confirmed complicated acute appendicitis, appendectomy with a histopathological finding of acute appendicitis after hospital discharge, or any complication of appendicitis requiring general anesthesia. Predefined secondary outcomes include later appendectomies, recurrence of histopathologically confirmed appendicitis and associated symptoms, postintervention complications, return to normal daily activities, quality of, resolution of appendicitis in US imagining after 1 month of symptomatic treatment, comparison of US and MRI findings at presentation, and differences in serum biomarkers and fecal microbiota composition.

Study Overview

• Status: Recruiting
• Conditions: Appendicitis
• Intervention / Treatment: Procedure: appendectomy

Detailed Description

While antibiotic treatment is an effective and safe treatment for most adults and children with imaging-confirmed uncomplicated acute appendicitis, emerging evidence further indicates that antibiotics and symptomatic treatment strategies may have similar efficacy and safety in uncomplicated acute appendicitis among adults. There are no randomized studies comparing appendectomy to symptomatic treatment in children.

The APPSYPP trial is a randomized national multicenter feasibility superiority pilot study comparing appendectomy with symptomatic treatment in children with imaging-confirmed uncomplicated acute appendicitis. Patients are recruited from all five Finnish university hospitals. Inclusion criteria are: 1) age 7-15 years, 2) imaging-confirmed uncomplicated acute appendicitis (no appendicolith, perforation, abscess, or tumor suspicion), and 3) CRP ≤ 65 mg/l. Patients are randomized to receive emergency appendectomy or symptomatic treatment. In the surgery group, patients undergo laparoscopic appendectomy within 18 hours after randomization. In order to ensure patient safety, symptomatically treated patients are hospitalized for at least 24 hours, and receive intravenous fluids and analgesics according to standard clinical practice. Primary outcome is treatment success at 30 days defined by not fulfilling any of the treatment failure criteria. In the surgery group, treatment failure is defined as normal appendiceal histopathology or any postintervention complication requiring general anesthesia. In the symptomatic treatment group, treatment failure is defined as inability to discharge from hospital without appendectomy within 48 hours after randomization with a finding of histopathologically inflamed appendix, appendectomy during the initial hospital stay due to clinical progression of appendicitis with histopathologically and surgically confirmed complicated acute appendicitis, appendectomy with a histopathological finding of acute appendicitis after hospital discharge, or any complication of appendicitis requiring general anesthesia.

The APPSYPP feasibility trial aims to assess the symptomatic treatment in children with imaging-confirmed uncomplicated acute appendicitis and whether this can safely be studied in a larger patient cohort in the future.

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Janne Suominen, MD, PhD; Phone Number: +358504272977; Email: janne.suominen@hus.fi
• Study Contact Backup: Name: Jenny Puputti; Email: jenny.puputti@helsinki.fi

Study Locations

• Finland
  • Helsinki, Finland
    • Recruiting
    • Helsinki University Central Hospital
    • Contact: Janne S Suominen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age 7-15 years
• clinical diagnosis of uncomplicated acute appendicitis confirmed by US and/or MRI: adequately visualized appendix with a diameter of 6.1-11.0 mm without evidence of perforation, abscess, appendicolith or tumor suspicion
• CRP ≤ 65 mg/l

Exclusion Criteria:

• inability to give informed consent
• age under 7 or over 15 years
• antibiotic administration within 14 days prior to enrolment
• any previous treatment for acute appendicitis
• severe nausea and/or vomiting preventing oral fluid intake
• systemic disease potentially compromising the safety of symptomatic treatment of acute appendicitis (e.g. type 2 diabetes, malignancy, immune deficiency, or a medical condition requiring immunosuppressant medication)
• diffuse peritonitis or complicated acute appendicitis at imaging (perforation, abscess, appendicolith or tumor suspicion)
• inadequately visualized appendix
• age and sex adjusted BMI over 27 kg/m2 and no MRI performed
• CRP > 65 mg/l.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Surgery; In the surgery group, patients undergo laparoscopic appendectomy within 18 hours after randomization.	Procedure: appendectomy; Laparoscopic appendectomy is performed within 18 hours after randomization in the surgery group. Patients in the symptomatic treatment group are carefully monitored and the same intervention (laparoscopic appendectomy) is performed in case of treatment failure.
Active Comparator: Symptomatic treatment; Symptomatically treated patients are hospitalized for at least 24 hours, and receive intravenous fluids and analgesics according to standard clinical practice.	Procedure: appendectomy; Laparoscopic appendectomy is performed within 18 hours after randomization in the surgery group. Patients in the symptomatic treatment group are carefully monitored and the same intervention (laparoscopic appendectomy) is performed in case of treatment failure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment success at 30d follow-up.	Treatment success is defined by not fulfilling any of the following treatment failure criteria. Treatment failure in the surgery group: Normal histopathology of the removed appendix.; Any complication of acute appendicitis or surgery requiring general anesthesia (GA) within 30 d. Treatment failure in the symptomatic treatment group: Inability to discharge from hospital within 48 h after randomization without appendectomy due to persisting symptoms and unmet discharge criteria with a finding of histopathologically inflamed appendix.; Appendectomy due to clinical suspicion of progressive appendicitis including increasing pain not responding to the defined non-opioid analgesics during the initial hospital stay with a finding of histopathologically and surgically confirmed complicated acute appendicitis.; Appendectomy with a histopathologically confirmed acute appendicitis after hospital discharge within 30 d.; Any complication of AA reiring GA within 30 d.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postintervention complications	Categorized according to Clavien-Dindo classification (Grades I-V).	1 year
Recurrent appendicitis	Recurrence of appendicitis (Histopathological diagnosis).	1 year
Recurrent symptoms	The number of emergency department visits or hospitalizations due to symptoms related to appendicitis.	1 year
Recovery of normal daily activities	Recovery to normal daily activities, school and sports. Reported in days.	1 year
QoL	Quality of life evaluated by PedsQL, a validated questionnaire	1 year
Resolution of acute appendicitis	Resolution of acute appendicitis, verified by US imaging.	1 month
Comparison of US and MRI in diagnostics	Comparison of US and MRI findings (appendix visibility/normal/uncomplicated/complicated appendicitis) at presentation in the same patient. Percentage (%) of patients with either normal appendix, uncomplicated appendicitis, complicated appendicitis or not visible appendix. Imaging modalities are compared to each other and with histopathological analysis. Whether MRI imaging can improve diagnostics.	1 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum biomarkers and fecal microbiota	Differences in serum biomarkers and fecal microbiota composition between treatment arms as an exploratory endpoint for future research. Serum biomarkers are investigated using proteomics and fecal microbiota composition is analyzed using a phylogenetic microarray. The microarray consists of oligonucleotide probes for the V1 and V6 regions on the 16S ribosomal RNA gene and summarized as abundancies of species-level, genus-level, and phylum-level groups.	1 month

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: Turku University Hospital; Oulu University Hospital; Kuopio University Hospital; Tampere University Hospital
• Investigators: Principal Investigator: Janne Suominen, MD, PhD, Helsinki University Central Hospital

Publications and helpful links

General Publications

• Puputti J, Suominen JS, Luoto T, Hiltunen P, Ripatti L, Nikoskelainen M, Nuutinen S, Sinikumpu JJ, Tahkola E, Porela-Tiihonen S, Hurme S, Salminen P, Pakarinen MP. A randomized, controlled multicenter feasibility pilot trial on imaging confirmed uncomplicated acute appendicitis: Appendectomy vs. symptomatic treatment in pediatric patients (the APPSYPP) trial study protocol. Contemp Clin Trials. 2022 Dec;123:106970. doi: 10.1016/j.cct.2022.106970. Epub 2022 Oct 22.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2023
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: February 8, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 21, 2022

Study Record Updates

• Last Update Posted (Actual): September 26, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: symptomatic treatment; uncomplicated acute appendicitis; spontaneous resolution
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Appendicitis
• Other Study ID Numbers: APPSYPP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All research data will be collected using an online REDCap database. Baseline data collection from all patients presenting with suspected acute appendicitis are collected in emergency department and all relevant data during the treatment and follow up.
• IPD Sharing Time Frame: 3 years
• IPD Sharing Access Criteria: Only partipating researchers have access to data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No