Antibiotics versus placebo in adults with CT-confirmed uncomplicated acute appendicitis (APPAC III): randomized double-blind superiority trial

Abstract

Background: Non-operative management of uncomplicated acute appendicitis is an option, but omission of antibiotics from the regimen has not been tested.

Methods: A double-blind, placebo-controlled, superiority RCT in adults with CT-confirmed uncomplicated acute appendicitis was designed to compare placebo with antibiotics (intravenous ertapenem followed by oral levofloxacin and metronidazole). The primary endpoint was treatment success (resolution resulting in discharge without appendicectomy within 10 days); secondary outcomes included pain scores, complications, hospital stay, and return to work.

Results: From May 2017 to September 2020, 72 patients with a mean(s.d.) age of 37.5 (11.1) years were recruited at five hospitals. Six were excluded after randomization (5 early consent withdrawals, 1 randomization protocol violation), 35 were assigned to receive antibiotics, and 31 to receive placebo. Enrolment challenges (including hospital pharmacy resources in an acute-care surgery setting) meant that only the lowest sample size of three predefined scenarios was achieved. The 10-day treatment success rate was 87 (95 per cent c.i. 75 to 99) per cent for placebo and 97 (92 to 100) per cent for antibiotics. This clinical difference of 10 (90 per cent c.i. -0.9 to 21) per cent was not statistically different for the primary outcome (1-sided P = 0.142), and secondary outcomes were similar.

Conclusion: The lack of antibiotic superiority statistically suggests that a non-inferiority trial against placebo is warranted in adults with CT-confirmed mild appendicitis. Registration number: EudraCT 2015-003634-26 (https://eudract.ema.europa.eu/eudract-web/index.faces), NCT03234296 (http://www.clinicaltrials.gov).

Fig. 1

Flow chart for APPAC III trial A total of 71 patients were eligible for the baseline comparison, and 66 for comparison of the primary endpoint. *Includes appendicolith, perforation, abscess, or suspicion of tumour. †Underwent ultrasound imaging, MRI or non-contrast-enhanced CT. ‡Diverticulitis (3 patients), ovarian cyst (7), hernia (2), pelvic inflammatory disease (2), other diagnosis (18). §Pregnancy, lactation, allergy to contrast media, kidney insufficiency, use of metformin, systemic illness, and inability to provide consent. ¶Withdrew consent after randomization but before receiving randomized treatment. #Operative or histopathological findings of appendicolith, gangrene, perforation, abscess, or tumour.