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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Appendicitis

Intervention / Treatment
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* Procedure: appendectomy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgery<br>In the surgery group, patients undergo laparoscopic appendectomy within 18 hours after randomization. | Procedure: appendectomy<br>* 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.<br>|
| Active Comparator: Symptomatic treatment<br>Symptomatically treated patients are hospitalized for at least 24 hours, and receive intravenous fluids and analgesics according to standard clinical practice. | Procedure: appendectomy<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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uncomplicated acute appendicitis, symptomatic treatment, spontaneous resolution