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:

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.