Efficacy of Non Operative Treatment With Amoxicillin/Clavulanic Acid Versus Surgical Treatment in Acute Uncomplicated Appendicitis in Children

The design of the NACAC study is an open-label, randomized, multicenter controlled non-inferiority trial with 2 parallel groups: one group of patients will have appendectomy (ST), and the other group will receive antibiotic treatment (NOT).

Children in the non-operative treatment group will be hospitalised for clinical monitoring with initiation of antibiotic therapy at day 1 with Amoxicillin/clavulanic acid IntraVeinous (IV) in 2 doses daily for a minimum of 24 hours and a maximum of 48 hours with a relay of Amoxicillin/clavulanic acid Per Os (PO) in 2 doses daily, for a total of 7 days (IV and PO).

Children can be discharged from hospital after day 1 if the clinical conditions are safe.

In case of hypersensitivity to antibiotic administered the patient will be withdrawn from the study.

Children randomised to the Surgical Treatment group will be hospitalised for a surgical usual management within 24 hours, according to the surgical unit organisation.

For all patients a physical examination (same as inclusion) will be made by an investigator at Day 1 and discharge. Questionnaires will be assessed at D1 and discharge. At discharge, parental absenteism will be evaluated. For ST group, possible post-operative complication will also be evaluated. A visit on the investigator site from Day 10 to Day 15 : all the patients will have a complete physical examination (same as inclusion), child activity evolution and parental absenteeism will be evaluated.

An abdominal ultrasound or CT scan will be performed in patients randomized in the non-operative treatment group. AE and concomitant treatment will be assessed at this study visit by questioning, during the physical examination of the patient.

Compliance to study treatment will be reviewed at day 12 in the NOT group. For ST group, possible post-operative complication will also be evaluated.

At Month 1 (D30), Month 6 (M6) and Month 12 (M12) investigator will realize phone visits in order to :

Get safety aspects related to antibiotic treatment and treatment-related failures at month 1, six months and one year, notably, secondary surgery and in ST group, a complication requiring anew general anaesthesia or possible post-operative complication, will be recorded.

Child activity evolution and parental absenteeism will also be recorded. AE and concomitant treatment will be recorded. A Cost-Utility analysis will be performed from the healthcare payer's perspective.This medico anlysis will need Direct medical costs collection based on security social system.

• Amoxi Clavulanate (Drug): children in the arm NOT
• appendicectomy (Procedure): children in usual care in arm Surgery

Primary outcomes

• Percentage of treatment-related failures at one year [12 months]: readmissions for suspicion of appendicitis, secondary surgery, emergency visits related to appendicitis management, postoperative infections, side effects of antibiotics, adverse events of anesthesia. In surgery group, a normal appendix based on pathology or a complication requiring a new general anaesthesia

Secondary outcomes

• Initial success rate [Day 12]
• Score of quality of life with the questionnaire EQ-5D-Y-3L for children [Day 1, Month 1 and Month 12.]: 0 is the worst score and 1 the better score (it is possible to have very bad values under 0)
• Score of of quality of life with the questionnaire EQ-5D-5L for parents [Day 1, Month 1 and Month 12.]: 0 is the worst score and 1 the better score (it is possible to have very bad values under 0)
• Direct Medical costs, and indirect costs (parental absenteeism) descriptions [Month 12]
• Rehospitalization, appendectomy [from Day 1 to Year 5]: Using consumption data available in SNDS database, describe child care pathways over 5 years
• Incidence of adverse events [At Month 1 and Month 12]: in the two groups, and incidence of adverse events due to antibiotics in the NOT group

Sex: All, ages: 5 Years to 14 Years

Inclusion Criteria:

* Age from 5 to <15 years-old
* Diagnosis of first episode of acute uncomplicated appendicitis confirming the diagnosis:
* an increase in the calibre of the appendix, measured at more than 6 mm in diameter and non-compressibility
* free fluid, echogenic fat, regional hyperemia
* performed in hospital or reviewed by local radiologist investigators if performed outpatient.
* Surgery expected within 24 hours after diagnosis
* Parental good understanding of the monitoring French instructions
* Free and informed consent, signed by both holders of parental authority/legal representative, with the accord of the minor patient.
* Affiliation to the health insurance plan

Exclusion Criteria:

* Ultrasound or CT scan showing one or several stercoliths, a plastron, an abscess or peritonitis
* Non-visualization of the appendix at ultrasound or CT scan
* Situations contraindicating surgery or anesthesia (patient for whom surgery and anesthesia would pose a life-threatening risk)
* Patients who have already received antibiotic therapy for acute appendicitis
* Known immunodepression, ongoing immunosuppressive treatment, diabetes
* Severe hematologic disorders (such as bone marrow failure, blood clotting disorders)
* History of proved allergy to Penicillin

  * History of proved allergy to amoxicillin and/or clavulanic acid
  * History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
  * History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid
  * History of allergy to any of the excipients listed in section 6.1 of each SmPC.
* On going antibiotherapy : previous antibiotherapy have to be stopped at least 48h before inclusion
* Parental refusal of research protocol
* Impossibility of home follow-up after discharge from hospital
* Pregnancy/ breastfeeding
* Simultaneously participation in another research study involving medicinal products
* Mental state rendering the person giving consent incapable of understanding the trial
* Parents being a relative of the investigator or a relative of someone from the team directly involved in the trial, including assistant doctors, pharmacists, nurses, and trial coordinators
* Renal insufficiency with creatinine clearance < 30mL/min
* Presence of an appendicolith

• Olivier ABBO, Study director, University Hospital of Toulouse