Oral Antibiotic Outpatient Therapy vs. Placebo in the Treatment of Uncomplicated Acute Appendicitis: a Randomized Double-blind Placebo-controlled Noninferiority Trial APPAC IV

Acute appendicitis is one of the most common surgical emergencies worldwide. For over a century, surgical removal of the appendix has been considered the only possible treatment option with appendectomy still being one of the most common emergency surgeries. Although appendectomy is generally well tolerated, it is a major surgical intervention and can be associated with postoperative morbidity. Since the time Fitz described the relationship between the appendix and pelvic abscess and McBurney demonstrated reduced morbidity from pelvic infections attributable to appendectomy, it has been thought that acute appendicitis invariably progresses to perforation strengthening the belief that emergency appendectomy is always required for acute appendicitis. However, it is now acknowledged that complicated and uncomplicated appendicitis are two different diseases both epidemiologically and clinically also suggesting different pathophysiology and the majority of the cases are uncomplicated. The differential diagnosis is essential as patients presenting with an uncomplicated acute appendicitis may not require surgical intervention and might experience even spontaneous resolution without perforation.

APPAC IV builds on trials by the APPAC (APPendicitis ACuta) study group showing that imaging confirmed uncomplicated acute appendicitis is in fact not a surgical emergency. Antibiotic therapy alone has been shown to be a safe and effective treatment option for patients with computed tomography (CT) confirmed uncomplicated acute appendicitis also in other randomized clinical trials (RCTs). A major knowledge gap on the role of antibiotics still exists. Changing the over century-old dogma of appendectomy for all appendicitis cases into current knowledge where the majority of patients with uncomplicated acute appendicitis can be treated with antibiotics alone if not only with symptomatic therapy, protecting patients from potential adverse effects of antibiotics. In any case, nonoperative treatment, i.e., avoiding unnecessary surgeries will result in major cost and resource savings as the majority of appendicitis cases are uncomplicated. In addition to direct cost savings demonstrated by the APPAC trial at both short- and long-term follow-up, the non-operative treatment approach in this very common surgical emergency allows for the re-allocation of limited health care resources.

Implementing the best available knowledge and current state-of-the-art diagnostics for uncomplicated acute appendicitis using uniform and standardized diagnostic criteria optimizing the pre-intervention patient selection, the investigators anticipate APPAC IV trial to have an even higher success rate of antibiotic treatment for imaging confirmed uncomplicated acute appendicitis compared to the previous trial. Future research should focus on determining both standardized uniform definitions differentiating between appendicitis severity ruling out complicated acute appendicitis and factors predicting non-responsiveness to antibiotics. Further optimizing the patient selection for non-operative treatment would enable potential outpatient management of uncomplicated acute appendicitis resulting in major hospital resource and cost savings. With the current knowledge provided by the landmark APPAC trials and other recent RCTs, initial antibiotic management is consistently associated with a lower complication rate and an at least 70% chance of avoiding surgery within the first year. This information should form the basis of shared informed decision-making.

Aims of the study and study hypothesis

APPAC IV, a randomized double-blind multicenter clinical trial comparing once daily oral moxifloxacin with placebo in an outpatient setting, assesses whether antibiotics and hospitalization or both can be omitted in the treatment of uncomplicated appendicitis further significantly increasing cost savings and patient satisfaction. This is a direct and ambitious research continuum to the previous three APPAC trials, which still have not solved the role and necessity of antibiotics. The APPAC IV is based on a novel concept of symptomatic treatment only further optimizing the possibilities of nonoperative treatment for uncomplicated acute appendicitis. After APPAC IV, it will be known whether antibiotics are needed. Bridging this knowledge gap will lay the foundation for clinical guidelines of nonoperative appendicitis treatment. In any outcome, there is a very high potential of both major health care cost and resource savings. If antibiotics are not needed, this will additionally result in significant reduction of antibiotic use in an extremely common surgical emergency. In addition, as AMR is a major global threat, the APPAC IV trial will include a translational MAPPAC II substudy at TUCH and UTU assessing the effects of antibiotics on gut microbiota, gut health, and correlation to serum cytokines in this real-life randomized patient cohort. As a part of ethical conduct of clinical trials, the investigators will use this unique opportunity of placebo vs. antibiotics randomized patients with the same disease in similar environments to investigate the development of AMR and the underlying bacterial defence mechanisms in Escherichia coli and across the microbiome.