The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial

The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial aims to test, if from a patient's perspective, the antibiotics strategy is "just as good as" surgery. The investigators believe that patients, clinicians, and the people who pay for healthcare (both patients and insurers) will find the antibiotics approach acceptable if 1) it results in high rates of treatment success, 2) does not increase complications, and 3) provides an equivalent or better patient experience. A large-scale non-inferiority trial is expected to result in a change in the management of one of the most common human illnesses. If non-inferiority is demonstrated (or superiority of the antibiotics approach identified), that finding will improve patient choice and should support a shift to the less invasive approach. If non-inferiority is not established, results may help to delineate the trade-offs between the two treatment approaches and inform decision-making.

The observation that patients with acute uncomplicated appendicitis (AUA) can be cured with antibiotics-alone has a scientific rationale. Traditionally, appendicitis was thought to result from a blockage of the appendix and that, if left untreated, inevitably led to a perforation. Contrary to this physiologic model, Carr demonstrated that obstruction of the appendix is an unlikely primary cause in the majority of patients and that most are caused by an enteric infection. A recent randomized trial found an increased rate of appendectomy with early use of computed tomography (CT) imaging and diagnostic laparoscopy, but case reports of appendicitis remission documented by serial CT all suggest that leaving the appendix in place does not inexorably lead to clinical compromise. A common concern of clinicians when considering treating AUA with antibiotics is that not removing the appendix may lead to perforation and complications from complicated appendicitis. Evidence suggests, however, that perforated appendicitis is a pre-hospital event and that non-perforated appendicitis is a "different" disease. This theory is supported by a general lack of relation between a delay in surgery of up to 24-36 hours and perforation rates. Most recently, Fusobacterium sp., a genus of enteric Gram-negative anaerobic bacteria, rather than an obstructive stone, was found to be correlated with the presence of appendicitis and the degree of inflammation. What remains to be determined is whether certain bacterial colonies or features of individual immune response are most associated with progression of appendicitis without appendectomy and whether successful outcomes for people undergoing antibiotics can be predicted based on the patient's characteristics.

An additional rationale for this study is to address limitations of prior trials. To avoid misclassification problems of other trials, all patients will undergo standard radiographic imaging including CT, ultrasound (US), or magnetic resonance imaging (MRI). Patients with an appendicolith will be included in the trial but considered a unique subgroup and will be evaluated as part of a pre-specified analysis (potentially excluding them from future recruitment if an early analysis demonstrates futility related to the primary antibiotic approach not being successful). To reflect usual and emerging techniques in treatment, the study includes both types of appendectomy (open and laparoscopic) and a broad range of antibiotic strategies including the option for an "all outpatient" treatment schedule with once daily dosing of longer-acting agents. Patients in the antibiotics arm will be given a minimum of 24 hours of intravenous (IV) antibiotics (using any appropriate dosing schedule and based on the patient's ability to tolerate oral medication), followed by oral antibiotics for a total of 10 days of antibiotic treatment). Discharge from the hospital or emergency department (ED) or a change in treatment arms will be guided by clinical targets and reasons for change in treatment arms will be assessed. Patients will be followed for up to two years to assess for longer-term complications, eventual appendectomy (performed anywhere), quality of life (QoL), gastrointestinal symptoms, and decisional regret. To quantify selection bias and to promote generalizability, all patients approached for the study and those who refuse randomization will be characterized at baseline. A parallel cohort of patients who refuse randomization (250 who initiate the antibiotics strategy and 250 who select the appendectomy strategy) will be surveyed for two years.

Inclusion criteria

• Adult ≥18 years;
• Clinical diagnosis of acute uncomplicated appendicitis (AUA) established by clinical care team, supported by any of the following usual care radiological tests (computed tomography (CT), ultrasound (US), and/or magnetic resonance imaging (MRI)). AUA is defined by the usual signs, symptoms, and imaging finding of appendicitis without:

• Diffuse peritonitis on clinical exam (i.e., rigid abdomen / four quadrant peritonitis);
• Radiologic findings of :

i. Free air; ii. Walled off fluid collection concerning for an abscess; iii. Significant amounts of intra-abdominal fluid throughout abdomen (i.e., more than trace fluid); or iv. Extent of inflammation or adjacent organ involvement on radiologic imaging such that appendectomy is relatively contraindicated.

• Ability to provide written or electronic informed consent in English or Spanish.

Exclusion criteria

• 1. Unable or unwilling to return or be contacted for clinical follow-up visits and/or research surveys;
• Currently incarcerated in a detention facility or in police custody (patients wearing a monitoring device can be enrolled) at baseline/screening;
• Evidence of severe sepsis or septic shock (e.g., new presumed sepsis-related organ dysfunction, elevated lactate, and/or fluid unresponsive hypotension);
• Conditions with altered immune response or at risk for bacterial seeding;
• Immunodeficiency (e.g., absolute neutrophil count <500/mm3, chronic immunosuppressive drugs, active chemotherapy or plans for chemotherapy in the following 30 days, or known acquired immune deficiency syndrome (AIDS) [cluster of differentiation 4 (CD4) count <200 or AIDS-defining illness within the last year] assessed by patient history);
• Uncompensated liver failure;
• Taking medication to treat active inflammatory bowel disease (e.g., Crohn's, ulcerative colitis);
• Malignancy, not in remission (ongoing chemotherapy patients excluded);
• Pregnant or expectation of becoming pregnant in the 30 days following baseline/screening;
• Expected concurrent hemodialysis, peritoneal dialysis, or treatments using indwelling venous catheters;
• Recent (within 90 days) placement of surgical implant (e.g., pacemaker, joint prosthesis, mechanical valve);
• Indwelling Left Ventricular Assist Device (LVAD);
• Patients with another infection (e.g., pneumonia, urinary tract infection) that requires treatment with another antibiotic at baseline/screening;
• Concurrent illness that would otherwise mandate hospitalization outside of appendicitis and associated symptoms at baseline/screening;
• Imaging findings of any of the following:

• Appendiceal soft-tissue mass;
• Imaging features of mucocele or tumor (e.g., appendix measuring ≥ 15mm in diameter and no other CT evidence of appendicitis);
• Concern for carcinomatosis on imaging; or
• Severe allergy or reaction (e.g., immediate urticaria or anaphylaxis) to all of the proposed antibiotics;
• Prior enrollment in the study or other investigational drug or vaccine while on study treatment;
• Abdominal/pelvic surgery in the past month; or
• More than seven hours have transpired since the patient received the first parenteral dose of antibiotics.