Clinical trial NCT02800785: The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial
Official title: The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Appendicitis
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
First posted: 2016-06-15
Enrollment: 1552
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Patient-reported Quality of Life as Measured by EuroQol (EQ-5D)
timeFrame: Four-weeks after randomization
Secondary outcomes:
measure: Total Number of Patients Who Had Resolution of Appendicitis Symptoms at 30 Days
timeFrame: at 30 days
measure: Rate of Participants With Perforated Appendicitis
timeFrame: 90 days post enrollment
measure: Number of Participants With at Least One Complications From Treatment
timeFrame: 90 days
measure: Rates of Participants With Appendiceal Cancer
timeFrame: Through study completion, up to 2 years
measure: Days in Hospital After Index Treatment Within 90 Days
timeFrame: 90 days post randomization
measure: Number of Clinic Visits or Emergency Room Visits
timeFrame: 90 days post randomization
measure: Eventual Appendectomy Incidence Proportion
timeFrame: 90 days post randomization
Other outcomes:
Locations:
city: Sylmar
country: United States
facility: Olive View-UCLA Medical Center
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Medicine- University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New York
country: United States
facility: New York University - Bellevue Hospital
state: New York
city: New York
country: United States
facility: New York University - Tisch Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Lyndon B Johnson- Harris Health
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Everett
country: United States
facility: Providence Regional Medical Center Everett
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Virginia Mason University Village Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center- First Hill
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center
state: Washington
Study officials:
affiliation: University of Washington
name: David R Flum, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: David A Talan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: CODA Collaborative; Flum DR, Davidson GH, Monsell SE, Shapiro NI, Odom SR, Sanchez SE, Drake FT, Fischkoff K, Johnson J, Patton JH, Evans H, Cuschieri J, Sabbatini AK, Faine BA, Skeete DA, Liang MK, Sohn V, McGrane K, Kutcher ME, Chung B, Carter DW, Ayoung-Chee P, Chiang W, Rushing A, Steinberg S, Foster CS, Schaetzel SM, Price TP, Mandell KA, Ferrigno L, Salzberg M, DeUgarte DA, Kaji AH, Moran GJ, Saltzman D, Alam HB, Park PK, Kao LS, Thompson CM, Self WH, Yu JT, Wiebusch A, Winchell RJ, Clark S, Krishnadasan A, Fannon E, Lavallee DC, Comstock BA, Bizzell B, Heagerty PJ, Kessler LG, Talan DA. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. N Engl J Med. 2020 Nov 12;383(20):1907-1919. doi: 10.1056/NEJMoa2014320. Epub 2020 Oct 5.
citation: Writing Group for the CODA Collaborative; Zhang IY, Voldal EC, Davidson GH, Liao JM, Thompson CM, Self WH, Kao LS, Cherry-Bukowiec J, Raghavendran K, Kaji AH, DeUgarte DA, Gonzalez E, Mandell KA, Ohe K, Siparsky N, Price TP, Evans DC, Victory J, Chiang W, Jones A, Kutcher ME, Ciomperlik H, Liang MK, Evans HL, Faine BA, Neufeld M, Sanchez SE, Krishnadasan A, Comstock BA, Heagerty PJ, Lawrence SO, Monsell SE, Fannon EEC, Kessler LG, Talan DA, Flum DR. Association of Patient Belief About Success of Antibiotics for Appendicitis and Outcomes: A Secondary Analysis of the CODA Randomized Clinical Trial. JAMA Surg. 2022 Dec 1;157(12):1080-1087. doi: 10.1001/jamasurg.2022.4765.
citation: Thompson CM, Voldal EC, Davidson GH, Sanchez SE, Ayoung-Chee P, Victory J, Guiden M, Bizzell B, Glaser J, Hults C, Price TP, Siparsky N, Ohe K, Mandell KA, DeUgarte DA, Kaji AH, Uribe L, Kao LS, Mueck KM, Farjah F, Self WH, Clark S, Drake FT, Fischkoff K, Minko E, Cuschieri J, Faine B, Skeete DA, Dhanani N, Liang MK, Krishnadasan A, Talan DA, Fannon E, Kessler LG, Comstock BA, Heagerty PJ, Monsell SE, Lawrence SO, Flum DR, Lavallee DC; Writing Group for the CODA Collaborative. Perception of Treatment Success and Impact on Function with Antibiotics or Appendectomy for Appendicitis: A Randomized Clinical Trial with an Observational Cohort. Ann Surg. 2023 Jun 1;277(6):886-893. doi: 10.1097/SLA.0000000000005458. Epub 2022 Jul 11.
citation: Writing Group for the CODA Collaborative; Talan DA, Moran GJ, Krishnadasan A, Monsell SE, Faine BA, Uribe L, Kaji AH, DeUgarte DA, Self WH, Shapiro NI, Cuschieri J, Glaser J, Park PK, Price TP, Siparsky N, Sanchez SE, Machado-Aranda DA, Victory J, Ayoung-Chee P, Chiang W, Corsa J, Evans HL, Ferrigno L, Garcia L, Hatch Q, Horton MD, Johnson J, Jones A, Kao LS, Kelly A, Kim D, Kutcher ME, Liang MK, Maghami N, McGrane K, Minko E, Mohr C, Neufeld M, Patton JH, Rog C, Rushing A, Sabbatini AK, Salzberg M, Thompson CM, Tichter A, Wisler J, Bizzell B, Fannon E, Lawrence SO, Voldal EC, Lavallee DC, Comstock BA, Heagerty PJ, Davidson GH, Flum DR, Kessler LG. Analysis of Outcomes Associated With Outpatient Management of Nonoperatively Treated Patients With Appendicitis. JAMA Netw Open. 2022 Jul 1;5(7):e2220039. doi: 10.1001/jamanetworkopen.2022.20039.
citation: Writing Group for the CODA Collaborative; Davidson GH, Monsell SE, Evans H, Voldal EC, Fannon E, Lawrence SO, Krishnadasan A, Talan DA, Bizzell B, Heagerty PJ, Comstock BA, Lavallee DC, Villegas C, Winchell R, Thompson CM, Self WH, Kao LS, Dodwad SJ, Sabbatini AK, Droullard D, Machado-Aranda D, Gibbons MM, Kaji AH, DeUgarte DA, Ferrigno L, Salzberg M, Mandell KA, Siparsky N, Price TP, Raman A, Corsa J, Wisler J, Ayoung-Chee P, Victory J, Jones A, Kutcher M, McGrane K, Holihan J, Liang MK, Cuschieri J, Johnson J, Fischkoff K, Drake FT, Sanchez SE, Odom SR, Kessler LG, Flum DR. Self-selection vs Randomized Assignment of Treatment for Appendicitis. JAMA Surg. 2022 Jul 1;157(7):598-608. doi: 10.1001/jamasurg.2022.1554.
citation: Davidson GH, Flum DR, Talan DA, Kessler LG, Lavallee DC, Bizzell BJ, Farjah F, Stewart SD, Krishnadasan A, Carney EE, Wolff EM, Comstock BA, Monsell SE, Heagerty PJ, Ehlers AP, DeUgarte DA, Kaji AH, Evans HL, Yu JT, Mandell KA, Doten IC, Clive KS, McGrane KM, Tudor BC, Foster CS, Saltzman DJ, Thirlby RC, Lange EO, Sabbatini AK, Moran GJ. Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment. BMJ Open. 2017 Nov 15;7(11):e016117. doi: 10.1136/bmjopen-2017-016117.