Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: The CODA Collaborative. A randomized trial comparing antibiotics with appendectomy for
appendicitis. N Engl J Med 2020;383:1907-19. DOI: 10.1056/NEJMoa2014320

(PDF updated April 22, 2021)

Supplementary Appendix for:

A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis

The CODA Collaborative

Table of contents

CODA Collaborative contributors.................................................................................................................................2

CODA sites and site leads ............................................................................................................................................4
Complete exclusionary criteria for the CODA trial .........................................................................................................6
Definitions of serious adverse events and serious morbidity events (defined using modified NSQIP criteria) ....................7
Stopping rules for the CODA trial .................................................................................................................................8
CODA trial per-protocol and missing data analyses ..................................................................................................... 10
Figure S1. Most common antibiotics in the CODA trial ................................................................................................ 11
Table S1. Inclusion of pre-specified outcomes in the CODA trial................................................................................... 12
Table S2. CODA enrollment ....................................................................................................................................... 13
Table S3. Sociodemographic and clinical characteristics (expanded) of CODA participants ............................................ 14
Table S4. Serious adverse events and serious morbidity-modified NSQIP criteria in the CODA trial ................................ 17

1
CODA Collaborative contributors

Writing group members:* David R. Flum, MD, MPH (UW), Giana H. Davidson MD, MPH (UW), Sarah E. Monsell,** MS

(UW), Nathan I. Shapiro, MD, MPH (BID), Stephen R. Odom, MD (BID), Sabrina E. Sanchez, MD, MPH (BMC), F. Thurston

Drake, MD, MPH (BMC), Katherine Fischkoff, MD (COL), Jeffrey Johnson, MD (HFH), Joe H. Patton, MD (HFH), Heather

Evans, MD, MS (HMC), Joseph Cuschieri, MD (HMC), Amber K. Sabbatini, MD, MPH (UW), Brett A. Faine, PharmD, MS

(IOW), Dionne A. Skeete, MD (IOW), Mike K. Liang, MD (LBJ), Vance Sohn, MD (MAD), Karen McGrane, MD (MAD),

Matthew E. Kutcher, MD, MS (MIS), Bruce Chung, MD (MMC), Damien W. Carter, MD (MMC), Patricia Ayoung-Chee, MD,

MPH (NYT/NYB), William Chiang, MD (NYT/NYB), Amy Rushing, MD (OSU), Steven Steinberg, MD (OSU), Careen S.

Foster, MD (PRE), Shaina M. Schaetzel, MD (PRE), Thea P. Price, MD (RUS), Katherine A. Mandell, MD, MPH (SWE), Lisa

Ferrigno, MD, MPH (UCD), Matthew Salzberg, MD, MBA (UCD), Daniel A. DeUgarte, MD (UCH), Amy H. Kaji, MD, PhD

(UCH), Gregory J. Moran, MD (UCO), Darin Saltzman, MD, PhD (UCO), Hasan B. Alam, MD (UOM), Pauline K. Park, MD

(UOM), Lillian S. Kao, MD, MS (UTH), Callie M. Thompson, MD (VAN), Wesley H. Self, MD, MPH (VAN), Julianna T. Yu, MD

(VM), Abigail Wiebusch, MD (VM), Robert J. Winchell, MD (WCM), Sunday Clark, ScD, MPH (WCM), Anusha Krishnadasan,

PhD (UCO), Erin Fannon, BA (UW), Danielle C. Lavallee, PharmD, PhD (UW), Bryan A. Comstock,** MS (UW), Bonnie

Bizzell, MBA, MEd (UW), Patrick J. Heagerty,** PhD, MS (UW), Larry G. Kessler, ScD (UW), David A. Talan, MD (UCRR).

Collaborators:* BID: Charles S. Parson; COL: Aleksandr M. Tichter, Randall Cooper; HFH: Lillian Adrianna Hayes, Alyssa

Hayward; HMC: Hikmatullah Arif, Laura Hennessey, Kelsey Pullar, Erika Wolff, Farhood Farjah; IOW: Cathy Fairfield;

LBJ-UTH: Tien C. Ko, Karla Bernardi, Oscar A. Olavarria, Naila H. Dhanani; MIS: Alan Jones, Rebekah K. Peacock,

Deepti Patki; MMC: David MacKenzie, Debra Burris, Joseph Mack, Terilee Gerry; NYT: Paresh Shah, Jason Maggi,

Mohamad Abouzeid; NYB: Marcovalerio Melis, Prashant Sinha, Kristyn Pierce; OSU: Jon Wisler; PRE: Brandon Tudor;

SWE: Julie Wallick, Ryan Martinez, Dayna Morgan, Sean Wells, John Tschirhart; UCD: Robert Mcintyre, Lauren Steward,

Tracey MacDermott, Kiran Dyamenahalli, Kelly Bookman; UCH: Brant Putnam, Ross Fleischman, Dennis Kim, Lara H.

Spence, Erin C. Howell; UCO: Lisandra Uribe, Kavitha Pathmarajah, Debbie Mireles, Melinda Gibbons, Robert Bennion,

Paul J. Schmit, Formosa Chen; UOM: Nathan Haas, Cindy Hsu, Krishnan Raghavendran; UW: Estell Williams, Karen

Horvath, Daniel Kim, Zoe Parr, Emily Voldal;** VAN: Kelly M. Moser, Karen F. Miller; VM: Scott Osborn; WCM: Billie

Johnsson, Lauren Mount.

2
*Site abbreviations: BID = Beth Israel Deaconess M edical Center, BM C = Boston University M edical Center, COL = Columbia University

M edical Center, HFH = Henry Ford Health System, HM C = Harborview M edical Center-UW M edicine, IOW = University of Iowa

Hospitals & Clinics, LBJ = University of Texas Lyndon B. Johnson General Hospital, M AD = M adigan Army M edical Center (affiliated

with University of Washington) M IS = University of M ississippi M edical Center, MMC = M aine Medical Center, NYB = Bellevue Hospital

Center NYU School of M edicine, NYT = Tisch Hospital NYU Langone M edical Center, OSU = Ohio State University Medical Center, PRE

= Providence Regional M edical Center Everett, RUSH = Rush University M edical Center, SWE = Swedish M edical Center, UCD =

UCHealth University of Colorado Hospital, Denver, UCH = Harbor University of California Los Angeles M edical Center, UCO = Olive

View University of California Los Angeles M edical Center, UCRR = UCLA Ronald Reagan M edical Center, UOM = University of M ichigan

M edical Center, UTH = University of Texas Health Science Center at Houston, UW = University of Washington M edical Center-UW

M edicine, VAN = Vanderbilt University M edical Center, VM = Virginia M ason M edical Center, WM C = Weill Cornell M edical Center

**M embers of the Writing Group and Collaborators involved in the analysis.

Executive Committee: Bonnie Bizzell, MBA, MEd (Chair, Patient Advisory Board); Bryan Comstock, MS (Operations

Director, Data Coordinating Center); Giana Davidson, MD MPH (Chair, Clinical Coordinating Center); Erin Fannon (Senior

Project Manager); David R. Flum, MD, MPH (Co-Principal Investigator); Patrick J. Heagerty, PhD, MS (Director, Data

Coordinating Center); Larry G. Kessler, ScD (Chair, Executive Committee); Anusha Krishnadasan, PhD (Project Manager,

California); Danielle C. Lavallee, PharmD, PhD (Director, Stakeholder Coordinating Center); Sarah Monsell, MS (Lead

Biostatistician); Kelsey Pullar, MPH (Research Coordinator Lead); David A. Talan, MD (Co-Principal Investigator); Erika

Wolff, PhD (Executive Director, SORCE (UW)).

Patient Advisory Board: Meridith Weiss, Kimberly Deeney, Heather VanDusen, Elliott Skopin, Mary Guiden, Miriam

Hernandez.

National Advisory Board: Emily E. Anderson, PhD, MPH; Darrell A. Campbell, Jr., MD; Fergal Fleming, MD; David B.

Hoyt, MD; J.J. Tepas III, MD (Deceased); Richard W. Whitten, MD; SreyRam Kuy, MD; Daniel S. Lessler, MD, MHA.

Data Safety and Monitoring Board: Karla Ballman, PhD; Thomas Diflo, MD; Bruce Wolfe, MD; Arden Morris, MD; Donald

Yealy, MD. Patient Advisors: Kathleen O’Connor, EdD; Olga Owens, N-PC.

3
CODA sites and site leads

Site Surgical Lead ED Lead

Bellevue Hospital Center New York University School of Patricia Ayoung-Chee, MD, William Chiang, MD
Medicine MPH
Beth Israel Deaconess Medical Center Charles Parsons, MD Nathan I. Shapiro, MD,
MPH
Stephen R. Odom, MD
Boston University Medical Center Sabrina E. Sanchez, MD, NA
MPH
F. Thurston Drake, MD, MPH
Columbia University Medical Center Katherine Fischkoff, MD Aleksandr Tichter, MD
Harbor-University of California Los Angeles Medical Daniel A. DeUgarte, MD Amy H. Kaji, MD, PhD
Center

Harborview Medical Center Heather Evans, MD, MS Amber K. Sabbatini, MD,

MPH
Joseph Cuschieri, MD
Henry Ford Health Hospital Jeffrey Johnson, MD NA
Joe H. Patton, MD
Madigan Army Medical Center Vance Sohn, MD Karen McGrane, MD
Maine Medical Center Damien W. Carter, MD NA
The Ohio State University Wexner Medical Center Steven Steinberg, MD NA
David Evans, MD
Olive View-University of California Los Angeles Medical Darin Saltzman MD, PhD David Talan, MD
Center
Gregory J. Moran, MD
Providence Regional Medical Center Everett Careen S. Foster, MD Brandon Tudor, MD
Rush University Medical Center Thea P. Price, MD NA
Swedish Medical Center Katherine A. Mandell, MD, NA
MPH
Tisch Hospital New York University Langone Medical Patricia Ayoung-Chee, MD, William Chiang, MD
Center MPH
UCHealth University of Colorado Hospital Lisa Ferrigno, MD, MPH Matthew Salzberg, MD,
MBA
University of Iowa Hospitals and Clinics Dionne A. Skeete, MD Brett A. Faine, PharmD,
MS

4
Site Surgical Lead ED Lead
University of Michigan Medical Center Pauline K. Park, MD NA
Hasan B. Alam, MD
University of Mississippi Medical Center Matthew E. Kutcher, MD, Alan Jones, MD
MS
University of Texas Health Science Center at Houston Lillian S. Kao, MD, MS NA
University of Texas Lyndon B. Johnson General Hospital Mike K. Liang, MD NA
University of Washington Medical Center Giana H. Davidson, MD, Amber K. Sabbatini, MD,
MPH MPH
Vanderbilt University Medical Center Callie M. Thompson, MD Wesley H. Self, MD, MPH
Virginia Mason Medical Center Abigail Wiebusch, MD Juliana T. Yu, MD
Weill Cornell Medical Center Robert J. Winchell, MD Sunday Clark, ScD, MPH

5
Complete exclusionary criteria for the CODA trial

Unable or unwilling to return or be contacted for 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); these patients can be enrolled if signs of sepsis resolve with fluid resuscitation
and pain medication administration while in the ED;

Immunodeficiency (e.g., absolute neutrophil count <500/mm3, chronic immunosuppressive drugs [e.g., oral
corticosteroids, anti-TNF agents], or known AIDS [i.e., recent CD4 count <200] assessed by patient history);

Diffuse peritonitis, radiographic evidence of severe phlegmon (if the surgeon determined a more significant operation
[e.g., ileocolectomy] was likely to be required), radiographic evidence of walled-off abscess, free air or more than
minimal free fluid;

Uncompensated liver failure;

Taking medication to treat active inflammatory bowel disease (e.g., Crohn’s, ulcerative colitis);

Active treatment for malignancy, not in remission (patients undergoing active chemotherapy or with plans for
chemotherapy in the following 30 days are 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 or at risk for
bacterial seeding of implants;

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 that would make the patient ineligible for one arm of the trial:

a. Appendiceal soft-tissue mass;

b. Imaging features of mucocele or tumor concerning for malignancy of the appendix or in other organs; or

c. Concern for any carcinomatosis on imaging;

Severe allergy or reaction (e.g., immediate urticaria or anaphylaxis) to all of the proposed antibiotics (See Section
4.5);

Prior enrollment in the study or taking 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.

6
Definitions of serious adverse events and serious morbidity events (defined using modified NSQIP criteria)
Serious adverse events
Severe antibiotic reaction
CVA or stroke
MI requiring treatment or cardiac arrest
Unplanned admit to ICU
Acute renal failure requiring dialysis
C. difficile colitis requiring colon resection
Pulmonary embolism requiring therapy
Coma >24 hours
Septic shock requiring pressors
Bleeding requiring transfusion
Newly infected prosthetic graft (e.g. infected cardiac valve, synthetic bypass graft infection secondary to appendicitis)
Mechanical ventilation >48 hours
Colostomy or ileostomy
Hospitalization other than for treatment of appendicitis
Death
Other life threatening event
Serious morbidity-modified NSQIP criteria
Deep incisional surgical site infection
Organ/space infection
Wound disruption surgical site infection
Intra-abdominal abscess
Sepsis
Septic shock
Bleeding requiring transfusion
Mild or moderate antibiotic reaction evaluated by a clinician in person
Pneumonia
Death
CVA or stroke
MI requiring treatment or cardiac arrest
Pulmonary embolism requiring therapy
Coma >24 hours
Renal insufficiency
Renal failure
Deep vein thrombosis requiring treatment
Tracheal reintubation/tracheostomy
Mechanical ventilation >48 hours
Major UTI (e.g., pyelonephritis)
Other, adjudicated adverse events
7
Stopping rules for the CODA trial

Based on data from prior studies, we anticipate that SAEs in the ITT antibiotics arm will be less common than in the
appendectomy arm. Since appendectomy is considered standard of care and it is desirable to assess effectiveness
within subgroups, we do not propose formal statistical stopping rules if SAE rates are lower in the antibiotics arm.
However, evidence of higher SAEs in the antibiotics arm will require DSMB consideration of the trial’s continuation. At
the planned interim analysis, we will use one-sided tests to formally compare the event rates across the two ITT
treatment groups using appropriate small sample methods such as Fisher’s exact test or Poisson regression with robust
standard errors for SAE per-patient counts. We will also monitor and compare the rates of SAEs in the appendectomy
arm to the rate of SAEs among patients in the observational cohort who receive appendectomy to address concerns
that surgery following antibiotic therapy may be associated with a higher surgical risk. For safety monitoring we will
utilize a one-sided Pocock stopping boundary38,39 (α=0.025) where, at the discretion of the DSMB and faculty
statistician, study recruitment may be discontinued if there is substantial statistical evidence for a higher safety event
rate in the antibiotics arm compared to the appendectomy arm (P<0.011 at either interim or final analysis). In other
words, the DSMB will consider stopping the trial on the basis of safety if there is substantial statistical evidence that
patients randomized to the antibiotics treatment are experiencing a higher rate of SAEs than patients randomized to
appendectomy.

Efficacy Monitoring – The DSMB will monitor patient-reported EQ-5D scores at four-weeks using a sequential monitoring
boundary for futility. Conditional power will be used to assess futility, the likelihood of the trial to show non-inferiority
at the final analysis. This will be done by calculating the probability of demonstrating non-inferiority in the ITT
analysis, conditional on the observed results and on assumptions about the future results of the trial. Using conditional
power for sequential monitoring of efficacy data, the type II error rate (β) for the study is bounded by β/(1-ε), where ε
denotes the conditional power monitoring threshold. At the recommendation of Bratton et al. (2012), the DSMB will
consider stopping the trial for futility (based on EQ-5D) if conditional power falls below a fixed threshold of ε=0.10.40
In other words, the trial would only stop on the basis of the EQ-5D if the EQ-5D in the antibiotics arm is worse than that
of patients randomized to appendectomy by a substantial margin. Futility analyses related to the EQ-5D will be
balanced by the DSMB against the need to determine the rates of early

Early Antibiotics Failures Monitoring – In a non-inferiority study, treatment with appendectomy in the antibiotics arm
may bias the study conclusions towards declaring non-inferiority of the antibiotics approach. In conjunction with safety
and PROs, the DSMB will review the rate of eventual appendectomy in the antibiotics arm as a measure of adherence to
protocol and study quality. No formal stopping rules are proposed on the basis of crossover or early antibiotics failure
rates overall or within subgroups.

Subgroup Monitoring – As an important clinical subgroup of interest, the DSMB will actively monitor patients with
appendicolith on safety, PROs, and the rate of treatment by appendectomy among those randomized to receive
antibiotics. No formal stopping rules are proposed based upon results observed within the appendicolith subgroup
because patient advisors determined that information for this substantial group of patients would be informative to
decision makers even if only a small proportion (<25%) had successful treatment with antibiotics. Another clinical
subgroup of interest includes patients treated with different antibiotic types and/or regimens and specifically those
who received completely outpatient versus at least some inpatient antibiotic therapy. The DSMB will actively monitor
8
patients based on antibiotics received and whether or not they ultimately had surgery. Subgroup monitoring will focus
on safety, PROs, and the rate of eventual appendectomy. No formal stopping rules are proposed based on results
observed within the antibiotic type and regimen subgroups since patient advisors determined that information for this
group of patients would be informative to decision makers.

DSMB Recommendations – After each interim review of the data, the DSMB will recommend one of the following
actions:

a. Continuation of the study as is;

b. Continuation of the study with protocol changes in the interest of safety or study accrual;

c. Discontinue the study due to inadequate patient accrual, follow-up, or study conduct;

d. Discontinue the study due to patient safety in the antibiotics arm; and

e. Discontinue the study for futility, low conditional power for the primary question of interest.

9
CODA trial per-protocol and missing data analyses

To address potential selection bias, we performed a secondary, treatment per-protocol analysis of EQ-5D at 90 days.
For the group assigned to antibiotics, per-protocol included the use of an IDSA/SIS recommended antibiotic, a
prescription for the full course, and, if an appendectomy was performed at index, that it was not reported as a
protocol violation. For those assigned to appendectomy, per protocol was defined as adherence to the randomization
assignment. The analysis used Inverse Probability Weighting 1 with robust standard errors. This analysis was also
adjusted for site and appendicolith status. We also conducted a sensitivity analysis using multivariate imputation by
chained equations (MICE) approach to impute missing data on our primary outcome.2 To inform the imputation we used
demographic and clinical factors collected at baseline and week 2 that were associated with either odds of having
missing data or with the primary outcome itself.

1. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology
2000;11(5):550-560.

2. van Buuren S, Groothuis-Oudshoorn K. MICE: multivariate imputation by chained equations in R. J Stat Softw
2011;45:1-67.

10
Figure S1. Most common antibiotics in the CODA trial

For initial intravenous use (at least 24 hours)

ertapenem
cefoxitin
or
metronidazole plus one of the following
ceftriaxone
cefazolin
levofloxacin

For oral use (remainder of 10 total days)

metronidazole plus one of the following
ciprofloxacin
cefdinir

11
Table S1. Inclusion of pre-specified outcomes in the CODA trial

Domain Inclusion

Primary outcome measure Included in paper

Clinical

Resolution of symptoms Included in paper

Appendectomy Included in paper

Perforated appendicitis Included in paper

Complications from treatment Included in paper

Appendiceal cancer Included in paper

Emergency department and urgent care visits Included in paper

Days using antibiotics beyond the initial treatment Included in paper

schedule

Clinic visits Included in paper

Patient-reported outcomes

PROMIS Global Health Short Form Will be in future

publication

Decision Regret Scale Will be in future

publication

Gastrointestinal Quality of Life Index (GIQLI) Will be in future

publication

Days of missed work Included in paper

12
Table S2. CODA enrollment

Site Screened Eligible (% of screened) Enrolled in RCT (% of eligible)

1 1002 662 (66%) 145 (22%)
2 840 569 (68%) 174 (31%)
3 655 440 (67%) 236 (54%)
4 584 292 (50%) 128 (44%)
5 564 342 (61%) 155 (45%)
6 489 311 (64%) 96 (31%)
7 416 270 (65%) 67 (25%)
8 414 196 (47%) 61 (31%)
9 358 234 (65%) 45 (19%)
10 354 296 (84%) 124 (42%)
11 331 131 (40%) 34 (26%)
12 261 193 (74%) 24 (12%)
13 243 119 (49%) 45 (38%)
14 242 107 (44%) 17 (16%)
15 238 62 (26%) 10 (16%)
16 226 157 (69%) 45 (29%)
17 191 142 (74%) 26 (18%)
18 183 125 (68%) 42 (34%)
19 156 103 (66%) 13 (13%)
20 88 75 (85%) 20 (27%)
21 85 34 (40%) 10 (29%)
22 78 53 (68%) 17 (32%)
23 72 26 (37%) 2 (8%)
24 66 53 (80%) 6 (11%)
25 32 20 (62%) 10 (50%)
Total 8168 5012 (61%) 1552 (31%)

13
Table S3. Sociodemographic and clinical characteristics (expanded) of CODA participants

Antibiotics Appendectomy
n= 776 n=776
Age (years)
Mean (SD) 38.3 (13.4) 37.8 (13.7)
18-29 255 (33%) 274 (35%)
30-39 220 (28%) 207 (27%)
40-49 151 (19%) 147 (19%)
50-59 93 (12%) 87 (11%)
60-69 43 (6%) 46 (6%)
70-79 13 (2%) 12 (2%)
80+ 1 (<1%) 3 (<1%)
Sex
Female 286 (37%) 290 (37%)
Male 490 (63%) 486 (63%)
Gender different from sex assigned at birth 8 (1%) 6 (1%)
Race
White 461 (60%) 449 (59%)
Black/African American 75 (10%) 63 (8%)
American Indian or Alaska Native 13 (2%) 9 (1%)
Asian 39 (5%) 53 (7%)
Native Hawaiian/Pacific Islander 4 (1%) 3 (<1%)
Multiple races 27 (4%) 26 (3%)
Other 149 (19%) 159 (21%)
Hispanic Ethnicity 362 (47%) 366 (47%)
Primary language
English 469 (60%) 464 (60%)
Spanish 267 (34%) 267 (34%)
Other 40 (5%) 45 (6%)
Employment status
Employed 570 (74%) 556 (72%)
Student 42 (5%) 43 (6%)
Not employed or other 161 (21%) 174 (23%)
Education status
Less than high school 163 (22%) 161 (21%)
High school graduate or GED 158 (21%) 151 (20%)
Some college 445 (58%) 452 (59%)
Insurance

14
 Antibiotics Appendectomy
n= 776 n=776
Commercial 323 (43%) 317 (42%)
Medicare/Tricare 89 (11%) 89 (11%)
Medicaid or other state program 134 (18%) 131 (17%)
Other or no coverage 213 (28%) 217 (29%)
Clinical characteristics
Modified Charlson Index 0.24 (0.53) 0.24 (0.53)
BMI 29.0 (6.6) 28.6 (6.1)
Duration of symptoms (days) 1.8 (3.6) 1.6 (1.6)
Alvarado score 6.6 (1.6) 6.7 (1.7)
History of fever 194 (25%) 185 (24%)
Initial WBC 12.9 (4.0) 13.4 (6.1)
Imaging
CT alone 626 (81%) 609 (78%)
US alone 24 (3%) 30 (4%)
More than one imaging test 125 (16%) 137 (18%)
Radiographic findings
Appendix maximum diameter 11.5 (2.9) 11.3 (2.8)
Appendicolith 212 (27%) 202 (26%)
Peri-appendiceal fat stranding 565 (75%) 556 (75%)
Severe fat stranding/phlegmon 19 (5%) 9 (1%)
Peri-appendiceal or pelvic fluid 196 (25%) 199 (26%)
Abscess/possible abscess 3 (<1%) 2 (<1%)
Perforation present or ambiguous 25 (3%) 26 (4%)
Note: n (%) is provided for all categorical variables and mean (SD) is provided for all continuous variables. SD=standard deviation,
GED=general equivalence degree, BM I=body mass index, WBC=white blood cell count, CT=computed tomography, US=ultrasound.
Charlson: comorbidity scale to predict morbidity and mortality. Score range: 0 to 40* with lower scores indicating less coexisting
conditions/less risk. *the range is 0-40 (though some studies seem to list 33 or 37 as the top of the range); studies use cut points of
4+ / 6+/ 8+ depending on population to show risk.
Alvarado Score: risk stratification for predicting acute appendicitis
Scoring: 10 point range with recommendations for scores 1-4 → discharge, 5-6 → observation, 7-10 → surgery
SD=standard deviation, GED=general equivalence degree, BM I=body mass index, WBC=white blood cell count, CT=computed
tomography, US=ultrasound
Details on missing data:
Data were missing for 8 participants in the antibiotics group and 14 participants in the appendectomy group for race or ethnic group;
26 and 30 participants, respectively, for gender different from sex assigned at birth; and 17 and 22 for insurance.
Employment status: Three participants randomized to antibiotics and three participants randomized to surgery were missing data
on employment status.
Education status: 10 participants randomized to antibiotics and 12 participants randomized to surgery were missing data on
education status.
Charlson: Three participants randomized to antibiotics and two participants randomized to surgery were missing data on the
Modified Charlson comorbidity index score.
BMI: 209 participants randomized to antibiotics and 104 participants randomized to surgery were missing data on body-mass index.

15
Duration of symptoms: One participant randomized to antibiotics and one participant randomized to surgery were missing data on
duration of symptoms.
Alvarado score: 38 participants randomized to antibiotics and 38 participants randomized to surgery were missing data on the
Alvarado score.
History of fever: No participants randomized to antibiotics and one participant randomized to surgery was missing data on history
of fever.
Initial white-cell count: Three participants randomized to antibiotics and one participant randomized to surgery were missing data
on initial white-cell count.
Appendix maximum diameter: 103 participants randomized to antibiotics and 114 participants randomized to surgery were missing
data on appendix maximum diameter.
Peri-appendiceal fat stranding and severe fat stranding/phlegmon: 25 participants randomized to antibiotics and 35 participants
randomized to surgery were missing data on peri-appendiceal fat stranding and severe fat stranding/phlegmon.
Peri-appendiceal or pelvic fluid: One participant randomized to antibiotics and two participants randomized to surgery were
missing data on peri-appendiceal or pelvic fluid.
Abscess/possible abscess: One participant randomized to antibiotics and two participants randomized to surgery were missing data
on abscess.
Perforation: 27 participants randomized to antibiotics and 47 participants randomized to surgery were missing data on perforation.
There were no missing data for age, sex, Hispanic ethnic group, primary language, or appendicolith.

16
Table S4. Serious adverse events and serious morbidity-modified NSQIP criteria in the CODA trial

Antibiotics Surgery
(n=676) (n=656)
Serious Adverse Events*
Severe antibiotic reaction 1 0
CVA or stroke 0 0
MI requiring treatment or cardiac arrest 0 0
Unplanned admit to ICU 4 0
Acute renal failure requiring dialysis 1 0
C. difficile colitis requiring colon resection 0 0
Pulmonary embolism requiring therapy 1 0
Coma >24 hours 0 0
Septic shock requiring pressors 1 0
Bleeding requiring transfusion 0 1
Newly infected prosthetic graft (such as a cardiac valve that gets infected or
synthetic bypass graft infection secondary to appendicitis) 0 0
Mechanical ventilation >48 hours 0 0
Colostomy or ileostomy 0 0
Hospitalization other than for treatment of appendicitis 19 19
Death 0 0
Other life threatening event 0 0
Total SAEs 27 20
Serious Morbidity-modified NSQIP criteria:
Deep incisional surgical site infection 1 0
Organ/space infection 7 2
Wound disruption surgical site infection 0 0
Intra abdominal abscess 27 14
Sepsis 11 1
Septic shock 2 0
Bleeding requiring transfusion 0 1
Severe antibiotic reaction** 1 0
Pneumonia 1 1
Death 0 0
CVA or stroke 0 0
MI requiring treatment or cardiac arrest 0 0
Pulmonary embolism requiring therapy 1 0

17
 Antibiotics Surgery
(n=676) (n=656)
Coma >24 hours 0 0
Renal insufficiency 0 0
Renal failure 2 0
Deep vein thrombosis requiring treatment 0 0
Tracheal reintubation/tracheostomy 0 0
Mechanical ventilation >48 hours 0 0
Major UTI (e.g., pyelonephritis) 1 1
Other, adjudicated adverse events*** 1 3
Total NSQIP 55 23
*Includes all reported severe adverse events regardless of whether they were determined by the site and
Independent Safety M onitor (ISM ) to be related to appendicitis treatment

**Defined as life-threatening by site and ISM ; modification of NSQIP

***In antibiotic arm: abscess drainage procedure; in surgery arm: abscess drainage procedure, allergic reaction
to pre-op cleaning solution, and acute chest pain, shortness of breath status post appendectomy

18