Appendectomy versus non-operative treatment for acute uncomplicated appendicitis in children: study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Nigel J Hall, Simon Eaton, Olivier Abbo, Alexis P Arnaud, Marianne Beaudin, Mary Brindle, Andreana Bütter, Dafydd Davies, Tim Jancelewicz, Kathy Johnson, Richard Keijzer, Eveline Lapidus-Krol, Martin Offringa, Nelson Piché, Risto Rintala, Erik Skarsgard, Jan F Svensson, Wendy J Ungar, Tomas Wester, Andrew R Willan, Augusto Zani, Shawn D St Peter, Agostino Pierro, Nigel J Hall, Simon Eaton, Olivier Abbo, Alexis P Arnaud, Marianne Beaudin, Mary Brindle, Andreana Bütter, Dafydd Davies, Tim Jancelewicz, Kathy Johnson, Richard Keijzer, Eveline Lapidus-Krol, Martin Offringa, Nelson Piché, Risto Rintala, Erik Skarsgard, Jan F Svensson, Wendy J Ungar, Tomas Wester, Andrew R Willan, Augusto Zani, Shawn D St Peter, Agostino Pierro

Abstract

Background: Appendectomy is considered the gold standard treatment for acute appendicitis. Recently the need for surgery has been challenged in both adults and children. In children there is growing clinician, patient and parental interest in non-operative treatment of acute appendicitis with antibiotics as opposed to surgery. To date no multicentre randomised controlled trials that are appropriately powered to determine efficacy of non-operative treatment (antibiotics) for acute appendicitis in children compared with surgery (appendectomy) have been performed.

Methods: Multicentre, international, randomised controlled trial with a non-inferiority design. Children (age 5-16 years) with a clinical and/or radiological diagnosis of acute uncomplicated appendicitis will be randomised (1:1 ratio) to receive either laparoscopic appendectomy or treatment with intravenous (minimum 12 hours) followed by oral antibiotics (total course 10 days). Allocation to groups will be stratified by gender, duration of symptoms (> or <48 hours) and centre. Children in both treatment groups will follow a standardised treatment pathway. Primary outcome is treatment failure defined as additional intervention related to appendicitis requiring general anaesthesia within 1 year of randomisation (including recurrent appendicitis) or negative appendectomy. Important secondary outcomes will be reported and a cost-effectiveness analysis will be performed. The primary outcome will be analysed on a non-inferiority basis using a 20% non-inferiority margin. Planned sample size is 978 children.

Discussion: The APPY trial will be the first multicentre randomised trial comparing non-operative treatment with appendectomy for acute uncomplicated appendicitis in children. The results of this trial have the potential to revolutionise the treatment of this common gastrointestinal emergency. The randomised design will limit the effect of bias on outcomes seen in other studies.

Trial registration number: clinicaltrials.gov: NCT02687464. Registered on Jan 13th 2016.

Keywords: Evidence Based Medicine; Gastroenterology; Paediatric Surgery.

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Clinical flow chart for APPY trial.

References

    1. St Peter SD, Sharp SW, Holcomb GW, et al. . An evidence-based definition for perforated appendicitis derived from a prospective randomized trial. J Pediatr Surg 2008;43:2242–5.
    1. Emil S, Laberge JM, Mikhail P, et al. . Appendicitis in children: a ten-year update of therapeutic recommendations. J Pediatr Surg 2003;38:236–42.
    1. Wilms IM, de Hoog DE, de Visser DC, et al. . Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane Database Syst Rev 2011;11:CD008359.
    1. Tiboni S, Bhangu A, Hall NJ, et al. . Outcome of appendicectomy in children performed in paediatric surgery units compared with general surgery units. Br J Surg 2014;101:707–14.
    1. Cheong LH, Emil S. Outcomes of pediatric appendicitis: an international comparison of the United States and Canada. JAMA Surg 2014;149:50–5.
    1. Eriksson S, Granström L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg 1995;82:166–9.
    1. Styrud J, Eriksson S, Nilsson I, et al. . Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial. World J Surg 2006;30:1033–7.
    1. Vons C, Barry C, Maitre S, et al. . Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomised controlled trial. Lancet 2011;377:1573–9.
    1. Salminen P, Paajanen H, Rautio T, et al. . Antibiotic therapy vs appendectomy for treatment of Uncomplicated acute appendicitis: the APPAC Randomized clinical trial. JAMA 2015;313:2340–8.
    1. Hansson J, Körner U, Khorram-Manesh A, et al. . Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg 2009;96:473–81.
    1. Mason RJ, Moazzez A, Sohn H, et al. . Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect 2012;13:74–84.
    1. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ 2012;344:e2156
    1. Blakely ML, Williams R, Dassinger MS, et al. . Early vs interval appendectomy for children with perforated appendicitis. Arch Surg 2011;146:660–5.
    1. St Peter SD, Aguayo P, Fraser JD, et al. . Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial. J Pediatr Surg 2010;45:236–40.
    1. Georgiou R, Eaton S, Stanton MP, et al. . Efficacy and safety of Nonoperative treatment for acute appendicitis: a Meta-analysis. Pediatrics 2017;139:e20163003
    1. Svensson JF, Patkova B, Almström M, et al. . Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg 2015;261:67-71.
    1. Chan AW, Tetzlaff JM, Altman DG, et al. . SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200–7.
    1. Moher D, Hopewell S, Schulz KF, et al. . CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869
    1. Schulz KF, Altman DG, Moher D, et al. . CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials 2010;11:32
    1. Gerber JS, Kronman MP, Ross RK, et al. . Identifying targets for antimicrobial stewardship in children's hospitals. Infect Control Hosp Epidemiol 2013;34:1252–8.
    1. Boers M, Idzerda L, Kirwan JR, et al. . Toward a generalized framework of core measurement areas in clinical trials: a position paper for OMERACT 11. J Rheumatol 2014;41:978–85.
    1. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205–13.
    1. DAMOCLES Study Group, NHS Health Technology Assessment Programme. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005;365:711–22.
    1. Ellenberg S, Fernandes RM, Saloojee H, et al. . Standard 3: data monitoring committees. Pediatrics 2012;129(Suppl 3):S132–S137.
    1. Hartling L, Wittmeier KD, Caldwell PH, et al. . StaR Child Health: developing evidence-based guidance for the design, conduct, and reporting of pediatric trials. Clin Pharmacol Ther 2011;90:727–31.
    1. Minneci PC, Sulkowski JP, Nacion KM, et al. . Feasibility of a nonoperative management strategy for uncomplicated acute appendicitis in children. J Am Coll Surg 2014;219:272–9.
    1. Gorter RR, van der Lee JH, Cense HA, et al. . Initial antibiotic treatment for acute simple appendicitis in children is safe: short-term results from a multicenter, prospective cohort study. Surgery 2015;157:916–23.
    1. Hall NJ, Kapadia MZ, Eaton S, et al. . Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: a systematic review. Trials 2015;16:275
    1. Mason RJ. Appendicitis: is surgery the best option? Lancet 2011;377:1545–6.
    1. Svensson JF, Patkova B, Almström M, et al. . Design of studies for Antibiotic treatment of acute appendicitis in Children: in support of RCTs. Ann Surg 2015:1
    1. Di Saverio S, Sibilio A, Giorgini E, et al. . The NOTA Study (Non Operative treatment for acute appendicitis): prospective study on the efficacy and safety of antibiotics (amoxicillin and clavulanic acid) for treating patients with right lower quadrant abdominal pain and long-term follow-up of conservatively treated suspected appendicitis. Ann Surg 2014;260:109–17.
    1. Minneci PC, Mahida JB, Lodwick DL, et al. . Effectiveness of Patient Choice in Nonoperative vs Surgical Management of Pediatric Uncomplicated acute appendicitis. JAMA Surg 2016;151:1–8.
    1. Kaneko K, Tsuda M. Ultrasound-based decision making in the treatment of acute appendicitis in children. J Pediatr Surg 2004;39:1316–20.
    1. Abeş M, Petik B, Kazil S. Nonoperative treatment of acute appendicitis in children. J Pediatr Surg 2007;42:1439–42.
    1. Armstrong J, Merritt N, Jones S, et al. . Non-operative management of early, acute appendicitis in children: is it safe and effective? J Pediatr Surg 2014;49:782–5.
    1. Koike Y, Uchida K, Matsushita K, et al. . Intraluminal appendiceal fluid is a predictive factor for recurrent appendicitis after initial successful non-operative management of uncomplicated appendicitis in pediatric patients. J Pediatr Surg 2014;49:1116–21.
    1. Hartwich J, Luks FI, Watson-Smith D, et al. . Nonoperative treatment of acute appendicitis in children: a feasibility study. J Pediatr Surg 2016;51:111–6.
    1. Steiner Z, Buklan G, Stackievicz R, et al. . A role for conservative antibiotic treatment in early appendicitis in children. J Pediatr Surg 2015;50:1566–8.
    1. Tanaka Y, Uchida H, Kawashima H, et al. . Long-term outcomes of operative versus nonoperative treatment for uncomplicated appendicitis. J Pediatr Surg 2015;50:1893–7.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever