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

NCT02800785 | Completed Results DMC

• 1 other identifier: STUDY00001155
• Study Type: interventional
• Target: 1,552
• Locations: 1 country
• Sites: 25

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.

Conditions

Appendicitis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Total Number of Patients Who Had Resolution of Appendicitis Symptoms at 30 Days

  at 30 days

• Rate of Participants With Perforated Appendicitis

  90 days post enrollment

• Number of Participants With at Least One Complications From Treatment

  90 days

• Rates of Participants With Appendiceal Cancer

  Through study completion, up to 2 years

• Days in Hospital After Index Treatment Within 90 Days

  90 days post randomization

Study Arms (2)

Antibiotics Therapy Arm

ACTIVE COMPARATOR

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

Appendectomy Arm

ACTIVE COMPARATOR

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

Interventions

Cefoxitin, Ertapenem, Moxifloxacin, Tigecycline, Ticarcillin-Clavulanic Acid; Metronidazole plus Cefazolin, Cefuroxime, Ceftriaxone, Cefotaxime, Ciprofloxacin, or Levofloxacin DRUG

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.

Antibiotics Therapy Arm

Appendectomy PROCEDURE

Appendectomy will be performed by an open or laparoscopic approach, depending on patient and surgeon preference.

Appendectomy Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• \. 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:

Sponsors & Collaborators

• University of Washington: lead
• Patient-Centered Outcomes Research Institute: collaborator

Study Sites (25)

Olive View-UCLA Medical Center

Sylmar, California, 91342, United States

Location

Harbor-UCLA Medical Center

Torrance, California, 90509, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Michigan Medicine- University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

New York University - Bellevue Hospital

New York, New York, 10016, United States

Location

New York University - Tisch Hospital

New York, New York, 10016, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

The Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Lyndon B Johnson- Harris Health

Houston, Texas, 77026, United States

Location

The University of Texas Health Science Center at Houston

Houston, Texas, 77026, United States

Location

Providence Regional Medical Center Everett

Everett, Washington, 98201, United States

Location

Harborview Medical Center

Seattle, Washington, 98104, United States

Location

Virginia Mason University Village Medical Center

Seattle, Washington, 98105, United States

Location

Swedish Medical Center- First Hill

Seattle, Washington, 98122, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Madigan Army Medical Center

Tacoma, Washington, 98431, United States

Location

Related Publications (7)

• 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.

  PMID: 33017106 BACKGROUND

• Serrano E, Voldal EC, Machado-Aranda D, DeUgarte DA, Kao L, Drake T, Winchell R, Cuschieri J, Krishnadasan A, Talan DA, Siparsky N, Ayoung-Chee P, Self WH, McGonagill P, Mandell KA, Liang MK, Dodwad SJ, Thompson CM, Padilla RM, Fleischman R, Price TP, Jones A, Bernardi K, Garcia L, Evans HL, Sanchez SE, Odom S, Comstock BA, Heagerty PJ, Lawrence SO, Monsell SE, Fannon EEC, Kessler LG, Flum DR, Davidson GH; Writing Group for the CODA Collaborative. Trial Participation and Outcomes Among English-Speaking and Spanish-Speaking Patients With Appendicitis Randomized to Antibiotics: A Secondary Analysis of the CODA Randomized Clinical Trial. JAMA Surg. 2023 Sep 1;158(9):901-908. doi: 10.1001/jamasurg.2023.2277.

  PMID: 37379001 DERIVED

• 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.

  PMID: 36197656 DERIVED

• 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.

  PMID: 35815898 DERIVED

• 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.

  PMID: 35796152 DERIVED

• 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.

  PMID: 35612859 DERIVED

• 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.

  PMID: 29146633 DERIVED

MeSH Terms

Conditions

Appendicitis

Interventions

Cefoxitin; Ertapenem; Moxifloxacin; Tigecycline; ticarcillin-clavulanic acid; Metronidazole; Cefazolin; Cefuroxime; Ceftriaxone; Cefotaxime; Ciprofloxacin; Levofloxacin; Appendectomy

Condition Hierarchy (Ancestors)

Intraabdominal Infections; Infections; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Cecal Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Cephamycins; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Carbapenems; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Nitroimidazoles; Nitro Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Cephacetrile; Ofloxacin; Digestive System Surgical Procedures; Surgical Procedures, Operative

Limitations and Caveats

Almost all patients with appendicitis were approached,\~30% of eligible patients agreed to undergo randomization, with variation across sites, and this factor may have introduced selection bias. As a pragmatic trial, the protocol did not specify requirements for hospitalization or for a given antibiotic regimen. The trial was not blinded. Some patients in the antibiotics group underwent appendectomy without meeting protocol-specified criteria for surgery

Results Point of Contact

• Title: Erin Fannon
• Organization: University of Washington

ecarney@uw.edu

206-685-9770

Study Officials

• David R Flum, MD, MPH

  University of Washington

  PRINCIPAL INVESTIGATOR

• David A Talan, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Surgery

Study Record Dates

• First Submitted: April 8, 2016
• First Posted: June 15, 2016
• Study Start: May 1, 2016
• Primary Completion: March 5, 2020
• Study Completion: September 1, 2021
• Last Updated: May 6, 2023
• Results First Posted: April 18, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share

Locations

US (25)