The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial
The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial
For the past 130 years, appendectomy has been the standard treatment for appendicitis. Recent
 studies from Europe have challenged the notion that surgery is the best option, showing that
 antibiotics alone can treat appendicitis without a need for appendectomy in as many as 3 out
 of 4 patients and without safety issues for up to one year of follow up. Despite these
 results, it remains to be determined if the antibiotic strategy is as good as an appendectomy
 for the outcomes that most patients care about. The Patient-Centered Outcomes Research
 Institute (PCORI)-funded Comparison of Outcomes of Drugs and Appendectomy (CODA) trial will
 be the first American, and largest-ever randomized trial of the issue and its results should
 help surgeons and patients make more informed healthcare decisions.
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:

 1. Adult ≥18 years;

 2. 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:

 1. Diffuse peritonitis on clinical exam (i.e., rigid abdomen / four quadrant
 peritonitis);

 2. 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.

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

 Exclusion Criteria:

 1. 1. Unable or unwilling to return or be contacted for clinical follow-up visits and/or
 research surveys;

 2. Currently incarcerated in a detention facility or in police custody (patients wearing
 a monitoring device can be enrolled) at baseline/screening;

 3. Evidence of severe sepsis or septic shock (e.g., new presumed sepsis-related organ
 dysfunction, elevated lactate, and/or fluid unresponsive hypotension);

 4. Conditions with altered immune response or at risk for bacterial seeding;

 5. 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);

 6. Uncompensated liver failure;

 7. Taking medication to treat active inflammatory bowel disease (e.g., Crohn's,
 ulcerative colitis);

 8. Malignancy, not in remission (ongoing chemotherapy patients excluded);

 9. Pregnant or expectation of becoming pregnant in the 30 days following
 baseline/screening;

 10. Expected concurrent hemodialysis, peritoneal dialysis, or treatments using indwelling
 venous catheters;

 11. Recent (within 90 days) placement of surgical implant (e.g., pacemaker, joint
 prosthesis, mechanical valve);

 12. Indwelling Left Ventricular Assist Device (LVAD);

 13. Patients with another infection (e.g., pneumonia, urinary tract infection) that
 requires treatment with another antibiotic at baseline/screening;

 14. Concurrent illness that would otherwise mandate hospitalization outside of
 appendicitis and associated symptoms at baseline/screening;

 15. Imaging findings of any of the following:

 1. Appendiceal soft-tissue mass;

 2. Imaging features of mucocele or tumor (e.g., appendix measuring ≥ 15mm in
 diameter and no other CT evidence of appendicitis);

 3. Concern for carcinomatosis on imaging; or

 16. Severe allergy or reaction (e.g., immediate urticaria or anaphylaxis) to all of the
 proposed antibiotics;

 17. Prior enrollment in the study or other investigational drug or vaccine while on study
 treatment;

 18. Abdominal/pelvic surgery in the past month; or

 19. More than seven hours have transpired since the patient received the first parenteral
 dose of antibiotics.