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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Appendicitis

Intervention / Treatment
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* Drug: Cefoxitin, Ertapenem, Moxifloxacin, Tigecycline, Ticarcillin-Clavulanic Acid; Metronidazole plus Cefazolin, Cefuroxime, Ceftriaxone, Cefotaxime, Ciprofloxacin, or Levofloxacin
* Procedure: Appendectomy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Antibiotics Therapy Arm<br>Patients in the antibiotics (abx) arm will receive a total of 10 days of abx, with a minimum of 24 hours using an IV abx formulation (administered in q8, q12, or q24 hour regimens with or without concurrent oral abx) followed by oral abx for the remainder of the 10 days. Patients will be offered a treatment regimen of abx based on guidelines published jointly by the Surgical Infection Society and the Infectious Disease Society of America. Any of the IV abx options (Single antibiotic-Cefoxitin, Ertapenem, Moxifloxicin, Tigecycline, Ticarcillin-Clavulanic Acid or Dual antibiotics-Metronidazole plus one of the following-Cefazolin, Cefuroxime, Ceftriaxone, Cefotaxime, Ciprofloxacin, Levofloxacin) will be considered acceptable. After IV abx, a regimen of oral abx will be continued for a total treatment length of 10 days. | Drug: Cefoxitin, Ertapenem, Moxifloxacin, Tigecycline, Ticarcillin-Clavulanic Acid; Metronidazole plus Cefazolin, Cefuroxime, Ceftriaxone, Cefotaxime, Ciprofloxacin, or Levofloxacin<br>* Patients will be offered a treatment regimen of antibiotics based on guidelines published jointly by the Surgical Infection Society and the Infectious Disease Society of America. After IV antibiotics are administered for a period of at least 24 hours, a regimen of oral antibiotics will be continued for a total treatment length of 10 days. Preferred oral antibiotic regimens include Moxifloxacin alone, and combinations such as Metronidazole or Clindamycin, for anaerobic bacteria coverage, plus Ciprofloxacin or Levofloxacin, or an oral Cephalosporin for aerobic Gram-negative bacteria coverage.<br>|
| Active Comparator: Appendectomy Arm<br>Patients in the appendectomy arm will have an appendectomy performed by an open or laparoscopic approach, depending on patient and surgeon preference. Prior to their operation, patients in this arm will receive one dose of antibiotics per currently accepted standards when appendicitis diagnosis is confirmed. Patients may also receive preoperative antibiotics per hospital standards for surgical infection prevention bundle. | Procedure: Appendectomy<br>* Appendectomy will be performed by an open or laparoscopic approach, depending on patient and surgeon preference.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-reported Quality of Life as Measured by EuroQol (EQ-5D) | The primary evaluation of patient-reported quality of life, as measured by the EuroQuol-5D at four-weeks, will be conducted using an intention-to-treat (ITT) analysis, where patients' data are analyzed according to the patients' randomized treatment assignment. EQ5D assesses health status in terms of five dimensions of health. The maximum score of 1 indicates the best health state, the minimum score is 0 (as score as bad as being dead). | Four-weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Number of Patients Who Had Resolution of Appendicitis Symptoms at 30 Days | Total Number of Patients who had resolution of appendicitis symptoms at 30 Days. This was measured as absence of fever and abdominal pain and tenderness. | at 30 days | 
| Rate of Participants With Perforated Appendicitis | Rates of patients who had perforated appendicitis will be calculated for each arm among those received an appendectomy. | 90 days post enrollment | 
| Number of Participants With at Least One Complications From Treatment | Comparison of the number of participants with at least one surgical complication and antibiotic complications. | 90 days | 
| Rates of Participants With Appendiceal Cancer | Rates of appendiceal cancer among participants will be calculated among the antibiotics and appendectomy arms. | Through study completion, up to 2 years | 
| Days in Hospital After Index Treatment Within 90 Days | Mean number of days in the hospital per participant calculated at 90 days post randomization. (Number of days/Number of Participants in Therapy Arm who responded to the 90 day survey question) | 90 days post randomization | 
| Number of Clinic Visits or Emergency Room Visits | Total number of participants with any visit to emergency department or urgent care clinic after index treatment within 90 days | 90 days post randomization | 
| Eventual Appendectomy Incidence Proportion | incidence proportion of appendectomy within 90 days post randomization among those randomized to antibiotics | 90 days post randomization |