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

Official title

Efficacy of Non Operative Treatment With Amoxicillin/Clavulanic Acid Versus Surgical Treatment in Acute Uncomplicated Appendicitis in Children: a Prospective Multicenter Randomized Controlled Non-inferiority Trial With Cost Utility Analysis

Overview

The majority of children with uncomplicated acute appendicitis may be considered for either a non-operative or an operative management. The antibiotic-first strategy appears effective as an initial treatment in 97% of children with uncomplicated AA (recurrence rate 14%), with Non Operative Treatment (NOT) also leading to less morbidity, fewer disability days, and lower costs than surgery. In this trial, the investigators will compare children randomised in a surgery group with children randomised in a NOT group (antibiotic strategy group). Children have 2 on-site visits (including surgery) in the first 12 days with recording of clinical datas and questionnaires, a phone visit at month 1, month 6, month 12 to collect concomitant treatment, Adverse Event (AE) and complications and parental questionnaires at the end of the study. A Cost-Utility analysis will be performed from the healthcare payer's perspective. The time horizon of the medico economic analysis was one year.

Detailed description

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In case of hypersensitivity to antibiotic administered the patient will be withdrawn from the study.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

Interventions

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

Primary outcome measures

• Percentage of treatment-related failures at one year [Time frame: 12 months]

Secondary outcome measures (6)

• Initial success rate [Time frame: Day 12]
• Score of quality of life with the questionnaire EQ-5D-Y-3L for children [Time frame: Day 1, Month 1 and Month 12.]
• Score of of quality of life with the questionnaire EQ-5D-5L for parents [Time frame: Day 1, Month 1 and Month 12.]
• Direct Medical costs, and indirect costs (parental absenteeism) descriptions [Time frame: Month 12]
• Rehospitalization, appendectomy [Time frame: from Day 1 to Year 5]
• Incidence of adverse events [Time frame: At Month 1 and Month 12]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 10 centers

• CHU de Bordeaux - Pellerin — Bordeaux
• Centre Hopsitalier Universitaire de Grenoble - Hôpital Nord — Grenoble
• Centre Hospitalier Universitaire de Lille - Hôpital Salengro — Lille
• Centre Hospitalier Universitaire de Limoges — Limoges
• AP-HM Hopital Nord — Marseille
• Centre Hospitalier Universitaire - Hôpital Lapeyronie — Montpellier
• Centre Hospitalier Universitaire de Nantes - Hôtel-Dieu — Nantes
• AP-HP Hôpital Trousseau — Paris
• … and 2 more centers

Identifiers

NCT: NCT07587450 · RC31/24/0320

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗