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



Status:Recruiting
Conditions:Gastrointestinal
Therapuetic Areas:Gastroenterology
Healthy:No
Age Range:18 - Any
Updated:11/18/2018
Start Date:May 2016
End Date:March 2021
Contact:Erin E Carney
Email:ecarney@uw.edu
Phone:206.685.9770

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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.

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.
We found this trial at
24
sites
1150 East Medical Center Drive
Ann Arbor, Michigan 48109
Principal Investigator: Hasan Alam, MD
Phone: 734-232-3813
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330 Brookline Ave
Boston, Massachusetts 02215
617-667-7000
Principal Investigator: Nathan Shapiro, MD
Phone: 617-754-2332
Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center (BIDMC) is one of the...
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Boston, MA
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7000 Fannin St
Houston, Texas 77030
(713) 500-4472
Principal Investigator: Lillian Kao, MD
University of Texas Health Science Center at Houston The University of Texas Health Science Center...
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Houston, TX
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2500 N State St
Jackson, Mississippi 39216
(601) 984-1000
Principal Investigator: Alan Jones, MD
Phone: 601-815-3008
University of Mississippi Medical Center The University of Mississippi Medical Center, located in Jackson, is...
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Jackson, MS
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1211 Medical Center Dr
Nashville, Tennessee 37232
(615) 322-5000
Principal Investigator: Wesley Self, MD
Phone: 615-343-1980
Vanderbilt Univ Med Ctr Vanderbilt University Medical Center (VUMC) is a comprehensive healthcare facility dedicated...
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22 Bramhall St
Portland, Maine 04102
(207) 662-0111
Principal Investigator: Damien Carter, MD
Phone: 207-662-2467
Maine Medical Center One of the country's consistently highest rated hospitals is right in your...
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1000 W Carson St
Torrance, California 90502
Principal Investigator: Amy Kaji, MD
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Torrance, CA
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13001 E. 17th Pl
Aurora, Colorado 80045
303-724-5000
Principal Investigator: Lisa Ferrigno, MD
Phone: 303-724-2757
University of Colorado Denver The University of Colorado Denver | Anschutz Medical Campus provides a...
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Boston, Massachusetts 02118
Principal Investigator: Frederick Drake, MD
Phone: 617-414-6836
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1653 W. Congress Parkway
Chicago, Illinois 60612
(312) 942-5000
Principal Investigator: Thea Price, MD
Phone: 312-942-1735
Rush University Medical Center Rush University Medical Center encompasses a 664-bed hospital serving adults and...
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Chicago, IL
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Columbus, Ohio 43210
Principal Investigator: Steven Steinberg, MD
Phone: 614-292-7146
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Detroit, Michigan 48202
Principal Investigator: Jeffrey Johnson, MD
Phone: 313-916-8006
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Everett, Washington 98201
Principal Investigator: Careen Foster, MD
Phone: 425-261-4075
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Houston, Texas 77026
Principal Investigator: Mike K Liang, MD
Phone: 713-566-5097
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200 Hawkins Dr,
Iowa City, Iowa 52242
866-452-8507
Principal Investigator: Brett Faine, PharmD, MS
Phone: 319-384-8335
University of Iowa Hospitals and Clinics University of Iowa Hospitals and Clinics—recognized as one of...
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New York, New York 10016
Principal Investigator: Patricia Ayoung-Chee, MD, MPH
Phone: 212-263-7797
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New York, New York 10016
Principal Investigator: Patricia Ayoung-Chee, MD, MPH
Phone: 212-263-7797
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630 W 168th St
New York, New York
212-305-2862
Principal Investigator: Katherine Fischkoff, MD
Phone: 212-342-0261
Columbia University Medical Center Situated on a 20-acre campus in Northern Manhattan and accounting for...
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2671 Northeast 46th Street
Seattle, Washington 98105
Principal Investigator: Richard Thirlby, MD
Phone: 206-341-1021
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325 9th Ave
Seattle, Washington 98104
(206) 744-3300
Phone: 206-685-9770
Harborview Medical Center Harborview Medical Center is the only designated Level 1 adult and pediatric...
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1101 Madison St #310,
Seattle, Washington 98104
(206) 386-6000
Principal Investigator: Katherine A Mandell, MD, MPH
Phone: 206-215-3986
Swedish Medical Center-First Hill Since 1910, Swedish has been the region's hallmark for excellence in...
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1959 NE Pacific St
Seattle, Washington 98195
(206) 598-3300
Phone: 206-685-9770
University of Washington Medical Center University of Washington Medical Center is one of the nation's...
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Sylmar, California 91342
Principal Investigator: David Talan, MD
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9040 Jackson Ave
Tacoma, Washington 98431
(253) 968-1110
Principal Investigator: Robert Rush, MD
Madigan Army Medical Center Located on Joint Base Lewis-McChord, Madigan Army Medical Center comprises a...
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