Conditions: Appendicitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1552
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Cefoxitin, Ertapenem, Moxifloxacin, Tigecycline, Ticarcillin-Clavulanic Acid; Metronidazole plus Cefazolin, Cefuroxime, Ceftriaxone, Cefotaxime, Ciprofloxacin, or Levofloxacin intervention 2: Appendectomy
Intervention descriptions: intervention 1: 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. intervention 2: Appendectomy will be performed by an open or laparoscopic approach, depending on patient and surgeon preference.

Protocol document:
Prot_000.pdf: 
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The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial 
 
Developed by the Collaborative of Acute Care Surgery and Medicine (CASM) Trialist Group 
Co-Directors David Talan, MD and David R. Flum, MD MPH  
 
 
Study Funder: 
Patient Centered Outcomes Research Institute (Principal Investigator-Flum) 
 
Version Number and Date: 
V1.0 – November 25, 2015 
V2.0 – April 3, 2016 
V3.0 – January X, 2017 
V3.5 – April 3, 2016  
     V5.0 April 2017 
V6.0 December 2018 
V6.1 February 2019 
 
 
 


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Table of Contents 
1.0 Key Personnel 
6 
2.0 Background and Rationale .................................................................................................... 8 
2.1 Rationale ...................................................................................................................... 8 
3.0 Study Aims and Methods .................................................................................................... 10 
3.1 Study Aims ................................................................................................................. 10 
3.2 Methods ..................................................................................................................... 10 
4.0 Participant Screening and Enrollment ................................................................................. 11 
4.1 Participant Screening ................................................................................................. 11 
4.1.1 Retrospective EMR review ........................................................................... 11 
4.2 Inclusion Criteria ......................................................................................................... 12 
4.3 Exclusion Criteria ....................................................................................................... 12 
4.4 Consent Process ........................................................................................................ 13 
4.4.1 Randomization Procedures .......................................................................... 14 
4.4.2 Those who Decline Randomization .............................................................. 14 
4.5 Antibiotics Therapy Arm ............................................................................................. 15 
4.5.1 Discharge Criteria ........................................................................................ 15 
4.5.2 Guidance for Appendectomy in Patients Randomized to Antibiotics............. 16 
4.6 Appendectomy Arm .................................................................................................... 16 
4.7 Discharge Instructions ................................................................................................ 16 
5.0 Study Schedule Overview, Research Assessments, Medical Record Review, Call Triggers, 
Withdrawal, Compensation, and Retention ....................................................................... 17 
5.1 Study Schedule Overview ........................................................................................... 17 
5.2 Research Assessments .............................................................................................. 18 
5.2.1 Baseline Assessment (Index Encounter) ...................................................... 18 


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5.2.2 Study Enrollment Post-Discharge Call ......................................................... 18 
5.2.3 Week 1 and Week 2 Assessments ............................................................... 19 
5.2.4 Week 4 Assessment .................................................................................... 20 
5.2.5 Follow-up Assessments (3, 6, 9, 12, 18, and 24 months) ............................. 20 
5.2.6 Optional Extended Follow-up Assessments (30, 36, 42, 48, 54, and 60 
months) ..................................................................................................... 21 
5.3 Medical Record Review .............................................................................................. 21 
Time points ........................................................................................................... 21 
Data Collection ..................................................................................................... 22 
5.4 Research Coordinator Call Triggers and Clinical Contact ........................................... 23 
5.4.1 Early Call Triggers (Up to 3 Months) ............................................................ 23 
5.4.2 Late Call Triggers (Beyond 3 Months) .......................................................... 23 
5.4.3 Clinician Education ...................................................................................... 24 
5.5 Reasons for Withdrawal ............................................................................................. 24 
5.5.1 Handling of Withdrawals .............................................................................. 24 
5.6 Compensation ............................................................................................................ 24 
5.6.1 Participant Compensation ............................................................................ 24 
5.6.2 Site and Site Lead Compensation ................................................................ 24 
5.7 Retention Activities ..................................................................................................... 25 
5.7.1 Maintaining Contact ..................................................................................... 25 
5.7.2 Contact between Assessments .................................................................... 25 
6.0 
Outcome Assessments..................................................................................................... 25 
6.1 Primary Outcome ....................................................................................................... 25 
6.2 Secondary Outcomes ................................................................................................. 26 
6.2.1 Clinical Complications .................................................................................. 26 


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6.2.2 Eventual Appendectomy .............................................................................. 27 
7.0 Data Management and Information Security ....................................................................... 27 
7.1 Data Management ...................................................................................................... 27 
7.1.2 Data Quality Monitoring ................................................................................ 27 
7.2 Information Security .................................................................................................... 28 
8.0 Statistical Analysis Plan and Stopping Rules ....................................................................... 29 
8.1 Randomization Overview ............................................................................................ 29 
8.2 Outcomes Measures .................................................................................................. 29 
8.3 General Analytic Strategy ........................................................................................... 30 
8.4 Missing Data............................................................................................................... 32 
8.5 Sample Size and Statistical Power ............................................................................. 32 
8.6 Data and Safety Monitoring Plan (DSMP) ................................................................... 33 
9.0 Study Related SAEs ............................................................................................................ 35 
9.1 Identification of SAEs ................................................................................................. 35 
9.2 SAE Reporting ............................................................................................................ 36 
9.3 Assignment of SAEs as Treatment Related ................................................................ 36 
10.0 Reporting Procedures ....................................................................................................... 36 
11.0 Quality and Performance Management Plans ................................................................... 37 
11.1 Quality Management Plan ........................................................................................ 37 
11.2 Performance Management Plan ............................................................................... 37 
11.3 Protocol Violations and Deviations ........................................................................... 38 
12.0 Protection of Human Participants ...................................................................................... 39 
13.0 Ancillary Studies................................................................................................................ 40 
14.0 References ........................................................................................................................ 40 


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1.0 Key Personnel 
 
Principal Investigators 
 
David R. Flum, MD MPH  
University of Washington  
Department of Surgery 
1959 NE Pacific Street, Box 356410 
Seattle, WA 98195 
Phone: 206-616-5440 
Email: daveflum@uw.edu 
 
David Talan, MD 
Olive View-UCLA Medical Center 
Department of Emergency Medicine 
14445 Olive View Drive, North Annex 
Sylmar, CA 91342 
Phone: 818-364-3107 
Email: dtalan@ucla.edu 
 
 
Director, Data Coordinating 
Center 
 
 
 
 
 
 
Director, Clinical 
Coordinating Center 
 
 
 
 
 
 
 
Director, Stakeholder 
Coordinating Center 
 
Patrick Heagerty, PhD 
University of Washington 
Department of Biostatistics 
4333 Brooklyn Avenue NE, Box 359461 
Seattle, WA 98105 
Phone: 206-616-2720 
Email: heagerty@uw.edu  
   
Giana H. Davidson, MD MPH  
University of Washington 
Department of Surgery 
1959 NE Pacific Street, Box 356410 
Seattle, WA 98195 
Phone: 206-543-9559 
Email: ghd@uw.edu  
 
Danielle Lavallee, PhD PharmD 
University of Washington 
Department of Surgery 
1107 NE 45th Street, Box 354808 
Seattle, WA 98105 
Phone: 206-221-1799 
Email: lavallee@uw.edu  


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Project Manager - 
Washington 
 
 
 
 
 
 
Project Manager - 
California 
Erin Carney 
University of Washington 
Department of Surgery 
1107 NE 45th Street, Box 354808 
Seattle, WA 98105 
Phone: 206-685-9770 
Email: ecarney@uw.edu  
 
Anusha Krishnadasan, PhD 
Olive View-UCLA Medical Center 
Department of Emergency Medicine 
14445 Olive View Drive, North Annex 
Sylmar, CA 91342 
Phone: 818-364-3111 
Email: idnet@ucla.edu  
 
 
 
 
 


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2.0 Background and Rationale 
For over 100 years, surgical removal of the appendix to treat acute appendicitis has been one of 
the most commonly performed procedures, resulting in nearly $2 billion in healthcare costs 
annually.1 Patients undergoing appendectomy miss a median of 10-14 days from work and only 
resume “normal” levels of activity 7-21 days after surgery.2 As an alternative to surgery, the 
successful use of antibiotics-alone as a treatment for acute uncomplicated appendicitis (AUA) 
was first reported in 1959 in a large British case series.3 As surgical procedures and anesthesia 
became safer, the antibiotics-only approach to appendicitis was usually restricted to patients 
with more complicated disease, usually followed by an interval appendectomy. The exception 
was patients who did not have access to prompt surgical services such as Naval submariners 
whose initial results were very satisfactory.4,5  
Inspired by the antibiotics-only approach results between 1956 and 2015, and with advances in 
radiologic imaging to diagnose and stage the progression of disease, there were six randomized 
trials comparing antibiotics to appendectomy among patients with AUA. These trials, all 
performed in Europe,6-11 found that nearly 3 out of 4 patients in the antibiotics treatment group 
avoided surgery in the first year after diagnosis. A meta-analysis of five of these studies (the 
most recent published in 2015) found that antibiotic treatment was associated with a 46% 
reduction in complications and less pain and disability than routine appendectomy.12 No 
participant deaths occurred in the trials, and the rates of perforation were lower among those in 
the antibiotic treatment group. However, existing trials suffer from important limitations. These 
include small sample sizes leading to indeterminate results, lack of imaging leading to potential 
inclusion of patients with complicated appendicitis and potentially without appendicitis at all, 
inexact and treatment dependent outcome definitions (rate of appendectomy) and operation/re-
operation criteria, arbitrarily prolonged hospitalization, limited use of laparoscopic techniques, 
inadequate antibiotic regimen activity, and short-term follow-up (no studies followed patients 
beyond one year). Furthermore, none of these trials included keeping a record of the patient’s 
experience with treatment in a standardized fashion. Perhaps as a result of these evidence 
gaps, nearly all United States (U.S.) patients with appendicitis (97.5% according to a recent 
California [CA]-based administrative database analysis13 and similar findings in Washington 
[WA] [personal communication DRF]) undergo appendectomy. Conversely, in Europe where the 
trials originated, it now appears that 1 in 5 patients with AUA are being offered the antibiotics 
approach. 
It remains to be determined whether patient experience with the antibiotics strategy (performing 
appendectomy only when the patient gets worse on antibiotics or has a recurrence of disease) 
is “just as good as” appendectomy. This comparison should consider the overall impact of the 
treatment on their health, well-being, quality of life (QoL), healthcare burden, and all clinical 
endpoints (e.g., resolution of symptoms, need for eventual appendectomy, complications). It 
also remains to be determined what patient and clinical factors are associated with worse 
outcomes.  
2.1 Rationale 
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. We 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 or adverse events (AEs), and 3) provides an equivalent or 
better patient experience. A large-scale non-inferiority trial is expected to result in a change in 


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February 2019 
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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 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.14 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.15 A 
concern of clinicians when considering treating AUA with antibiotics is that not removing the 
appendix may put patients at risk for a more complicated operation and higher morbidity. 
Evidence suggests, however, that perforated appendicitis is a pre-hospital and pre-antibiotic 
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 among patients with 
appendicitis who are treated with antibiotics and perforation rates.16,17 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.18 What remains to be determined is whether certain bacterial colonies or 
features of individual immune response are most associated with progression of appendicitis 
and whether successful outcomes for people undergoing antibiotic management 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 and consistent with U.S. norms,, 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 arm will be guided by clinical targets and reasons for change in treatment 
arms will be assessed. Participants will be followed for up to two years to assess for longer-term 
complications, eventual appendectomy (performed anywhere), 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 (up to 250 who initiate the antibiotics 
strategy and 250 who select to undergo the appendectomy strategy) will be surveyed for up to 
two years. Participants in all cohorts will be given the option to participate in an extended follow-
up that will assess long term complications, eventual appendectomy, QoL, and gastrointestinal 
symptoms. 


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3.0 Study Aims and Methods 
3.1 Study Aims 
Aim 1. Compare patient reported outcomes (PROs) in patients randomized to the antibiotics or 
appendectomy strategy.  
Sub Aim 1. Compare PROs in patients without appendicolith randomized to the antibiotics or 
appendectomy strategy. 
Exploratory Aim A. Assess the rate of eventual appendectomy after starting the 
antibiotics treatment regimens in the first week, early (1-4 weeks) and late (2-24 months) 
periods and identify patient clinical characteristics (e.g., appendicolith) as well as 
clinician and practice site characteristics associated with eventual appendectomy in the 
antibiotic therapy group. 
Aim 2. Compare clinical outcomes in patients randomized to antibiotics versus appendectomy. 
Sub Aim 2. Compare clinical outcomes in patients without appendicolith randomized to the 
antibiotics or appendectomy strategy. 
Exploratory Aim B. Compare randomized patients to those in a concurrent observational 
cohort to identify selection characteristics and outcome differences between the 
two groups. 
The central hypotheses of the CODA trial is that PROs among patients in the antibiotics arm will 
not be inferior to those in the appendectomy arm and that adverse clinical outcomes will not be 
significantly worse (non-inferior) among patients being treated with antibiotics. 
3.2 Methods  
This will be a multi-site, open trial in which participants with AUA are randomized to one of 
two initial treatment strategies, appendectomy or antibiotics (with appendectomy only for those 
with a deteriorating clinical condition while being treated with antibiotics or disease recurrence).  
The University of Washington’s (UW) Surgical Outcomes Research Center (SORCE) will lead a 
Clinical Coordinating Center (CCC) and Stakeholder Coordinating Center (SCC). The UW 
Center for Biomedical Statistics (CBS) will serve as the Data Coordinating Center (DCC).  
The CCC will coordinate all aspects of the trial. Investigators at SORCE will coordinate the 
study at the University of Washington Medical Center (UWMC) and up to twenty other clinical 
sites. Investigators at Olive View-UCLA Medical Center in CA will coordinate the study there 
and up to four other clinical sites. In preparing for the study, 18 potential hospital sites were 
engaged and up to 20 will be considered for involvement in the study, based on readiness of 
infrastructure, staff engagement, patient population characteristics, and number of appendicitis 
cases. 
Prior to study initiation and enrollment, all clinicians and staff who encounter patients with 
possible appendicitis will complete study-specific training including demonstrating successful 
use of the antibiotics strategy in five patients and site experience recorded in a non-protected 
health information (PHI) based registry (www.certain.org/appysurvey) or log reviewed with the 
study leadership team. All staff engaging patients with appendicitis at all study sites will undergo 
online and in-person educational and orientation sessions for the topic and the study protocol.  
Table 1. Potential Study Sites, Characteristics, and Projected Yearly Volume of Appendicitis. 


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4.0 Participant Screening and Enrollment 
4.1 Participant Screening  
Patients presenting to the ED will be screened by study investigators and/or study coordinators 
seven days a week based on alerts from clinicians, staff, or screening of ED logs. Patients will 
be identified as potential candidates for the study based on inclusion and exclusion criteria 
collected as part of standard care, including confirmatory diagnostic imaging (CT, US, and/or 
MRI).  
The CODA Screening Form must be completed for all patients ≥18 years of age presenting to 
the ED (hospital/clinic) with presumptive diagnosis of appendicitis that has not been previously 
treated. Completion and data-entry of this form is required regardless of patient eligibility to 
ensure a complete description of the population of interest. Those who do not meet eligibility 
criteria or have exclusion criteria present will be considered ineligible. Additionally, this form 
must be completed and entered for patients that were not approached.  
Sites are responsible for maintaining their own screening log in accordance with their 
institutional policies and guidelines. This log should document adequate information such that 
the research team may disclose to the institutional compliance department that a patient’s 
electronic medical record (EMR) was accessed to screen for potential eligibility for the CODA 
trial. UW Medicine requires disclosure of accessing the EMR for purposes other than treatment, 
payment, and health care operations.  
Sites are required to provide a monthly de-identified appendicitis census to the UW CCC. This 
census will be compared to the number of participants reported as screened at each site and 
will serve as a measure of protocol compliance.  
4.1.1 Retrospective EMR review  
For patients excluded due to concern for appendiceal cancer or mass, an EMR review that is 
separate from the scheduled CODA participants EMR review will be completed. This EMR 
review may be done retrospectively and must be done in accordance with site Institutional 
Review Board (IRB) recommendations and approvals. The intention of this EMR review is to 
Female
> 65 
Years
Medicaid
Hispanic
Black
Asian
AI/AN*
Pacific 
Islander
Harborview 
47
13 (27.7)
2 (4.3)
12 (25.5)
12 (25.5)
7 (14.9)
7 (14.9)
2 (4.3)
4 (8.5)
Madigan Army
107
33 (53.6)
16 (15.0)
0 (0.0)
4 (3.7)
4 (3.7)
2 (1.9)
0 (0.0)
1 (0.9)
Northwest 
77
36 (46.8)
14 (18.2)
8 (10.4)
2 (2.6)
6 (7.8)
6 (7.8)
0 (0.0)
0 (0.0)
Providence  
294
147 (50.0)
54 (18.4)
47 (16.0)
26 (8.8)
6 (2.0)
16 (5.4)
5 (1.7)
3 (1.0)
Sacred Heart
180
91 (50.6)
35 (19.4)
18 (10.0)
2 (1.1)
4 (2.2)
2 (1.1)
4 (2.2)
1 (0.6)
Skagit Valley 
93
57 (61.3)
21 (22.6)
17 (18.3)
20 (21.5)
3 (3.2)
1 (1.1)
2 (2.2)
0 (0.0)
Swedish
386
179 (46.4)
67 (17.4)
20 (5.2)
35 (9.1)
11 (2.9)
39 (10.1)
0 (0.0)
3 (0.8)
University of Washington 
85
38 (44.7)
14 (16.5)
12 (14.5)
8 (9.4)
1 (1.2)
10 (11.8)
2 (2.4)
0 (0.0)
Virginia Mason 
87
41 (47.1)
26 (29.9)
2 (2.3)
4 (4.6)
3 (3.5)
8 (9.2)
1 (1.2)
2 (2.3)
Olive View-UCLA 
221
85 (38.5)
2 (0.9)
173 (78.3)
183 (82.8)
2 (0.9)
6 (2.7)
0 (0.0)
4 (1.8)
Harbor-UCLA 
263
112 (42.6)
4 (1.5)
116 (44.1)
229 (87.1)
19 (7.2)
8 (3.0)
0 (0.0)
0 (0.0)
Los Angeles County+USC 
360
148 (41.1)
23 (6.4)
133 (36.9)
236 (65.6)
54 (15.0)
21 (5.8)
1 (0.3)
1 (0.3)
All Sites
2200
980 (44.5)
278 (12.6)
558 (25.4)
761 (34.6)
120 (5.5)
126 (5.7)
17 (0.8)
19 (0.9)
Medical Center
Total 
n/yr
N (%)


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fully characterize this particular patient population and to better understand whether or not the 
CT reading appropriately excludes patients.  
EMR review for these patients will include review and abstraction of the following patient 
records: final pathology report, operative report, radiology images and reports that indicate 
association with cancer. 
EMR review will be completed for patients excluded for the following reasons: 1) appendiceal 
soft-tissue mass, 2) imaging features of mucocele or tumor, 3) concern for any carcinomatosis 
on imaging, or 4) qualitative reason indicative of concern for cancer or mass.  
Sites will be provided with a list of screening IDs for patients who were ineligible due to the 
aforementioned reasons. 
4.2 Inclusion Criteria  
1. Adult ≥18 years; 
2. First clinical diagnosis of AUA established by clinical care team, supported by any of the 
following usual care radiological tests (CT, US, and/or MRI). AUA is defined by the usual 
signs, symptoms, and imaging finding of appendicitis without: 
a. Diffuse peritonitis on clinical exam (i.e., rigid abdomen / four quadrant peritonitis); 
b. 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 urgent appendectomy is relatively contraindicated or 
not intended.  
3. Ability to provide written informed consent in English or Spanish. 
4.3 Exclusion Criteria 
Participants must not have any of the following exclusion criteria:  
1. Unable or unwilling to return or be contacted for 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); these patients can 
be enrolled if signs of sepsis resolve with fluid resuscitation and pain medication 
administration while in the ED; 
4. 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); 
5. Uncompensated liver failure; 


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6. Taking medication to treat active inflammatory bowel disease (e.g., Crohn’s, ulcerative 
colitis);  
7. Active treatment for malignancy, not in remission (patients undergoing active 
chemotherapy or with plans for chemotherapy in the following 30 days are excluded); 
8. Pregnant or expectation of becoming pregnant in the 30 days following 
baseline/screening;  
9. Expected concurrent hemodialysis, peritoneal dialysis, or treatments using indwelling 
venous catheters or at risk for bacterial seeding of implants; 
10. Recent (within 90 days) placement of surgical implant (e.g., pacemaker, joint prosthesis, 
mechanical valve); 
11. Indwelling Left Ventricular Assist Device (LVAD);  
12. Patients with another infection (e.g., pneumonia, urinary tract infection) that requires 
treatment with another antibiotic at baseline/screening;  
13. Concurrent illness that would otherwise mandate hospitalization outside of appendicitis 
and associated symptoms at baseline/screening;  
14. 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; 
15. Severe allergy or reaction (e.g., immediate urticaria or anaphylaxis) to all of the 
proposed antibiotics (See Section 4.5); 
16. Prior enrollment in the study or other investigational drug or vaccine while on study 
treatment; 
17. Abdominal/pelvic surgery in the past month; or 
18. More than seven hours have transpired since the patient received the first parenteral 
dose of antibiotics. 
4.4 Consent Process 
The research coordinator and a representative from the medical team will confirm the patient’s 
eligibility for the study based on inclusion and exclusion criteria. A research team member will 
approach all eligible patients and ask them to review an informed decision making video using a 
handheld device. The English or Spanish-language video explains both treatment options and 
the research study using linguistically and culturally appropriate language. In the event that the 
tablet is malfunctioning or the patient declines to watch the video, the research coordinator will 
provide an informational pamphlet that includes the same content as the video. There are two 
versions of the video and pamphlet, one focused on positive messaging, the other negative. 
Participants who present on odd calendar days will be shown Version 1; those who present on 
even days will be shown Version 2. Which version was shown to the patient will be documented 
on the screening form in order to determine whether phrasing outcomes in different ways 
impacts subject participation. The video and informational pamphlet both conclude with a 


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request of the patient to read and sign an informed consent document for participation in the 
randomization cohort. 
a. For patients consenting to randomization, they will be randomly assigned to 
either the antibiotics or appendectomy arm immediately following consent and 
assigned a study ID; 
b. Patients refusing consent to randomization may first be invited to participate in 
the observational cohort, and if that is declined, may then be offered participation 
in the EMR review cohort. This will be done by separate consent(s) with the 
participant selecting one of two participation options:  
o Option 1. Observational cohort (no randomization). Participants selecting 
the observational cohort will be asked to complete the same research 
assessment activities as the randomized cohort and will have their 
appendicitis treated following the same treatment protocols.  
o Option 2. EMR review cohort. Participants selecting this option will be 
followed by passive EMR review only. They will not be contacted again 
for study purposes and will not be asked to complete the Baseline 
Assessment or the Follow-Up Assessments described in Section 5.2. 
In summary, depending on the site, there will be two or three consents for this study with the 
option to participate in the following groups: 1) randomization cohort, 2) observational cohort, 
and 3) EMR review cohort. Participants may only consent to one study group. The 
randomization consent will be presented to the patient following the informed decision-making 
video or material presentation. Patients declining randomization will then be presented with a 
different consent form to consider participation in the observational and EMR review only 
cohorts. 
Consenting participants will also need to complete a Health Insurance Portability and 
Accountability Act (HIPAA) form in accordance with their institutional guidelines. For some 
partnering sites, HIPAA language will be incorporated into the informed consent document but 
for others, this will be a separate document. For example, the UW requires that a participant 
sign a separate HIPAA document to indicate consent that their EMR is accessed and reviewed 
for research purposes. The HIPAA form is not reviewed by the UW’s Human Subjects Division 
but is required per UW Medicine policy. 
4.4.1 Randomization Procedures 
After informed consent, participants will be randomized to appendectomy or to antibiotics using 
computer generated assignments. Randomization will be based on a random number 
sequence, stratified by site and presence of appendicolith, and will also be blocked to assure 
balance across treatment groups. Randomization failures (defined as a patient who agreed to 
randomization but whose treatment was allocated in a non-random fashion or was randomized 
under inaccurate information) will be recorded as protocol violations and these consenting 
participants will continue to be followed. Their outcomes will be recorded and examined in a 
separate sub-analysis. 
4.4.2 Those who Decline Randomization 
Depending on the site, participants who decline randomization will be approached to provide 
consent to the observational cohort. As many as 500 will be consented into an observational 


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cohort study. Recruitment will be capped by treatment choice, site location, and time. Once the 
cap has been reached, participants will be offered participation in the EMR review only cohort.   
4.5 Antibiotics Therapy Arm 
Patients in the antibiotics arm will receive a total of 10 days of antibiotics, with a minimum of 
24 hours using an IV antibiotic formulation (administered in q8, q12, or q24 hour regimens with 
or without concurrent oral antibiotics) followed by oral antibiotics for the remainder of the 
10 days. 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.19 The first dose of antibiotics will be given in the ED at the time of diagnosis of 
appendicitis for both treatment arms. This flexibility in antibiotics choice is not expected to 
impact outcome but should improve the generalizability of the results, and therefore, 
implementation of the findings. Any of the IV antibiotics options (Single antibiotic-Cefoxitin, 
Ertapenem, Moxifloxicin, Tigecycline, Ticarcillin-Clavulanic Acid or Dual antibiotics-
Metronidazole or Clindamycin plus one of the following-Cefazolin, Cefuroxime, Ceftriaxone, 
Cefotaxime, Ciprofloxacin, Levofloxacin) will be considered acceptable. At many sites, these will 
be administered to inpatients only. For clinicians and patients interested in outpatient receipt of 
antibiotics, the available options will include Ertapenem or Moxifloxacin (q24) alone or 
Ceftriaxone (IV) plus IV or oral Metronidazole or Clindamycin, as tolerated. Although these 
antibiotics are considered acceptable and equally efficacious for intra-abdominal infections by 
the aforementioned professional societies, outcomes based on antibiotics used and antibiotics 
regimen will be monitored at regular intervals by the DCC and reported to the Data and Safety 
Monitoring Board (DSMB) for consideration in protocol modification. After IV antibiotics are 
administered for a period of at least 24 hours, a regimen of oral antibiotics will be continued to 
complete a total treatment length of 10 days. Acceptable oral regimens should be based on in 
vitro activity against aerobic and anaerobic Gram-negative bacteria known to cause 
appendicitis, and practical experience with oral antibiotic regimens used to treat diverticulitis. 
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 
will be prescribed by clinicians and procured by patient as per usual clinical care.  
4.5.1 Discharge Criteria  
Beginning after adequate evaluation of a patient following treatment, clinical staff will have the 
option to discharge the patient if they meet specific criteria: 
1. Stable and near normal vital signs appropriate for age; 
2. Afebrile; 
3. Signs and symptoms controlled with oral analgesics; 
4. Patient able to tolerate oral fluids (e.g., water, broth) and medication;  
5. Patient and clinician (emergency physician and surgery team agreement) report that 
discharge is acceptable; and 
6. Routine clinical follow-up visit confirmed.  


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4.5.2 Guidance for Appendectomy in Patients Randomized to Antibiotics  
For participants randomized to the antibiotics arm, appendectomy will be recommended when 
there is: 
1. Development of diffuse peritonitis;  
2. Development of severe sepsis/septic shock (e.g., new presumed sepsis-related organ 
dysfunction, elevated lactate, and/or fluid unresponsive hypotension)and/or 
3. Worsening signs and symptoms of appendicitis after 48 hours following the first 
antibiotics dose.  
Absent these criteria, patients will be encouraged to continue with the antibiotics treatment 
strategy, especially during the first 48 hours of treatment. At any point after initiating the 
antibiotics strategy, the surgeon and patient can determine that an appendectomy should be 
performed. When a decision for appendectomy is being considered, the site lead investigator 
will be notified to determine if any of the above criteria are met or, if not, to review the surgeon’s 
and patient’s specific reasons for recommending (surgeon) or requesting (patient) 
appendectomy.  These reasons will be recorded for analysis and reviewed by the project 
manager. If the project manager believes an appendectomy was recommended by the surgeon 
outside of the protocol, it will be reviewed by a clinician not otherwise affiliated with the study 
who will follow up with the site PI. All appendectomies performed outside of study protocol, 
other than those requested by the participant, will be reported as protocol violations. 
All participants will be encouraged to return to the hospital or clinic site if they have recurrent 
signs and symptoms of appendicitis after the four-week assessment and encouraged to 
undergo repeat diagnostic imaging to detect recurrent appendicitis. Participants in the antibiotics 
arm who return to any of the study sites during the follow-up period (but after the four-week 
assessment) with recurrent appendicitis will be offered appendectomy or the option of another 
attempt at antibiotics but will not be re-randomized or moved to another cohort.  
4.6 Appendectomy Arm 
All patients randomized to appendectomy will receive one dose of antibiotics per currently 
accepted standards described in Section 4.5 when diagnosis is confirmed in the ED. Patients 
may also receive preoperative antibiotics per hospital standards for surgical infection prevention 
bundle.  
Appendectomy will be performed by an open or laparoscopic approach, depending on patient 
and surgeon preference.  
4.7 Discharge Instructions 
The same criteria for discharge will be applied to the antibiotics group and the appendectomy 
group (Section 4.5.1) including standard discharge instructions and return precautions, 
telephone or in-person appointments for usual clinical care follow-up (one to three weeks after 
discharge), and contact information for the study coordinator and surgeon or emergency 
medicine investigator at that site. Participants will also be provided with 24-hour hospital/clinic 
paging information for a clinician at their site should they have any emergent clinical concerns.  
 


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5.0 Study Schedule Overview, Research Assessments, Medical Record Review, Call 
Triggers, Withdrawal, Compensation, and Retention 
5.1 Study Schedule Overview 
Consenting participants will be asked to complete research assessments on the topics and at 
the time points described in Table 2. Site research coordinators (RCs) will oversee the 
completion of the Baseline Assessment in-person and will also contact participants by phone to 
complete the Week 1 and Week 2 Assessments. Participants will then be contacted by phone, 
mail, or email by the UW study staff to complete the Week 4 Assessment, Quarterly 
Assessments for the first year, and Biannual Assessments in the second year after the 
participant’s initial ED presentation. 
Participants will be given the option to consent to extended follow-up beyond the two-year mark. 
These participants will be surveyed annually for another 3 years for a total follow-up period of 5 
years.  
Table 2. Participant Assessment Schedule. 
Item 
Baseline 
Follow-Up Time Point 
Optional Extended 
Follow-up 
First 4 
Weeks 
Month 
Month 
1 
2 
4 
3 
6 
9 
12 
18 
24 
36 
48 
60 
Patient Point of Contact 
Site RC 
Site 
RC 
UW study staff (Site RC as backup) 
UW study staff 
Contact Information 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
EQ-5D20 
x 
  
  
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
10-PROMIS Global 
Health Short Form21 
x 
  
  
x 
x 
  
  
x 
x 
x 
x 
x 
x 
PROMIS-Pain Intensity 
x 
x 
x 
  
  
  
  
  
  
  
  
  
  
Symptom Onset 
x 
  
  
  
  
  
  
  
  
  
  
  
  
Beyond Demographics* 
x 
  
  
  
  
  
  
  
  
  
  
  
  
Treatment 
Satisfaction/Expectation 
x 
  
  
x 
x 
  
  
  
  
  
  
  
  
Gastrointestinal Quality 
of Life (GIQLI)22 
  
  
  
x 
x 
  
  
x 
x 
x 
x 
x 
x 
Healthcare Utilization 
  
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Signs & Symptoms of 
Appendicitis 
  
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
  
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Decision Regret Scale23 
  
  
  
x 
x 
  
  
x 
  
  
  
  
  
Major Life Changes 
  
  
  
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
Work Productivity Index 
  
x 
x 
x 
x 
  
  
  
  
  
 
 
 
Return to Work 
Information 
  
x 
x 
x 
x 
  
  
  
  
  
 
 
 
Medication Use  
  
x 
x 
x 
x 
  
  
  
  
  
 
 
 
Treatment Strategy 
Change 
  
x 
x 
x 
  
  
  
  
  
  
 
 
 


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*Includes the following topics: Demographics & Gender Identify, Caregiver Role, Instrumental Support, 
Employment/Student Status, Income, Pain Catastrophizing, Health Literacy, Social Support, Confidence in Treatment 
Success, Trust in Healthcare 
 
To ensure successful retention of participants and completion of research assessments through 
the follow-up period, detailed contact information including name, address, phone numbers, 
email addresses, as well as alternate contact persons and phone numbers will be requested 
from participants at baseline (and updated at subsequent time points). While complete contact 
information is ideal to optimize future retention, only one means of contacting the participant is 
required for enrollment. For participants with upcoming travel plans abroad or who may live 
internationally, it is preferred that they provide phone and email contact information as mailed 
contact is slow and costly for the short windows around each research assessment.  
The Week 1 and Week 2 follow-up assessments will be conducted by the site RCs. All 
subsequent follow-up assessments (Week 4 through the end of the follow-up period) will be 
managed and conducted by the UW study staff. The UW study staff are located in Seattle, WA. 
The UW study staff specialize in operationalizing multi-modal participant outreach and has 
dedicated research staff to support research studies conducted by UW investigators. For each 
timepoint, if a completed survey has not been received at the end of the standard outreach, UW 
staff and/or the site research coordinators will make additional outreach attempts.  
5.2 Research Assessments 
5.2.1 Baseline Assessment (Index Encounter)  
For all participants consenting to the randomized or observational cohorts, the research 
coordinator will support the participant as they complete the Baseline Assessment described in 
Table 2 (above). The Baseline Assessment should be completed in-person and prior to 
revealing the participant’s random treatment assignment; however, research coordinators 
are asked to document when the participant became aware of their assignment, should it be 
revealed prior to completion of the Baseline Assessment. Survey questions will be presented in 
the order of importance in the event that the participant is unable to complete the full battery of 
questionnaires. The research coordinator will also extract case report data from the medical 
record related to the index hospital visit. 
5.2.2 Study Enrollment Post-Discharge Call 
Twenty-four to forty-eight hours after enrollment a member of the research team will attempt to 
contact all participants to determine their current health status, answer any questions about the 
study, and to review the survey protocol. All patients will be encouraged to attend a usual care, 
in-person, or phone-based follow-up clinical assessment within two weeks of discharge. This 
clinic or phone-based contact with clinical staff is considered part of usual care and is not a 
research assessment.  
At the time of enrollment and at the 48-hour contact, all participants will be given the study 
coordinator’s contact information and will be encouraged to contact them with any questions or 
concerns. Participants will also be reminded of the 24-hour hospital/clinic paging information for 
a clinician at their site should they have any emergent clinical concerns.  
Participants will be instructed at enrollment to contact the clinical team for return to clinic or the 
ED if they experience signs and symptoms of a complication. They will be evaluated by the site 


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lead clinician or their designee if they present to the ED or clinic for an unscheduled visit related 
to appendicitis at any time during the study period. 
No in-person visits beyond those related to usual clinical care will be required as part of this 
protocol. As such, research-related clinical care charges will not be generated. 
5.2.3 Week 1 and Week 2 Assessments 
Participants will be asked about the following at Weeks 1 and 2: 
1. Treatment strategy change;  
2. General clinical follow-up; 
3. Self-reported complications and AEs, including diarrhea; 
4. Medication use, specifically: 
a. Pain medications (to estimate morphine equivalent dose used); and 
b. Number of antibiotic doses that were taken and number of remaining pills; 
5. Return to work/school/regular activities; 
6. Healthcare utilization including: 
a. Details on hospitalizations, clinic, standard of care healthcare visits, and ED visits 
and estimated time spent in healthcare; 
b. Use of repeat imaging during follow-up; 
c. Signs and symptoms of recurrent appendicitis; 
d. Appendectomy during follow-up period and reason (recurrence or 
elective/interval); and 
e. Out of pocket expenses. 
 
Research coordinators will contact participants by phone to complete the Week 1 (contact 
window = days 7-10) and Week 2 (contact window = days 14-17) Assessments. (Day 0 is the 
day of study enrollment). Research coordinators will initiate outreach by phone on the day the 
window opens for each assessment period. If necessary, up to two calls may be made each 
day. These calls will be made at varying times of the day in an effort to reach the participant 
(e.g., morning or mid-day and again, after business hours).  
If the contact protocol is exhausted and participant contact is not made, the corresponding 
assessment will be missed and attempts to contact the participant will resume as per contact 
protocol at the next assessment time point.   
During the Week 2 Assessment, research coordinators will remind participants that they will be 
contacted by UW study staff to complete the remainder of their research assessments. 
Participants will be reminded that they are welcome to contact their research coordinator at any 
time if any questions or concerns should arise. UW study staff will communicate with the 
research coordinator to ensure appropriate reporting is completed should an AE or complication 
be reported to them. 


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5.2.4 Week 4 Assessment 
In addition to the measures noted in Section 5.2.1, the following additional measures will be 
collected at the Week 4 Assessment (day 26-day 56): 
1. European Quality of Life-5 Dimensions (EQ-5D) Quality of Life;20 
2. 10 Patient Reported Outcomes Measurement Information System (PROMIS) Global 
Health Short Form;21 
3. Decision Regret Scale;23 
4. Gastrointestinal Quality of Life Index (GIQLI);22 
5. Work Productivity Index; and 
6. Treatment satisfaction. 
Self-reported complications or AEs will be recorded. Any serious adverse events (SAEs) will be 
communicated to the relevant site study team to ensure appropriate reporting is completed. 
UW study staff will contact the participant to complete the Week 4 Assessment. UW study staff 
will initiate a contact protocol approximately 26 days after the participant’s initial ED 
presentation. This protocol will include a combination of phone, mail, and email as determined 
by the contact information provided by the participant. If the contact protocol is exhausted and 
the assessment has not been completed, the participant’s research coordinator will be notified. 
They will review the EMR and provide any site-specific or EMR-specific updates that may be 
helpful; for example, an updated telephone number. Additional contact attempts (calls, emails, 
texts, etc) will be scheduled . These contact attempts will be made at varying times of the day in 
an effort to reach the patient (e.g., morning, mid-day, after business hours) and may be made 
by either the UW staff or the site staff. If the assessment is still not completed, it will be 
considered missed and attempts to contact the participant will resume as per contact protocol at 
the next assessment time point.   
5.2.5 Follow-up Assessments (3, 6, 9, 12, 18, and 24 months) 
At regular quarterly intervals through 12 months, then at 18 months and 24 months, the 
following will be assessed using phone, mail, or web-based surveys: 
1. Complications, signs and symptoms related to appendicitis and related healthcare 
utilization, time spent in healthcare, time away from work/school, out of pocket expenses 
(3, 6, 9, 12, 18, 24 months);  
2. Work Productivity Index (3 months); 
3. EQ-5D20 and 10-PROMIS21 (3, 6, 9, 12,18, 24 months); 
4. GIQLI22 (3,12,18, 24 months); and 
5. Decision Regret Scale23 (3,12 months). 
UW study staff will contact the participant to complete the quarterly and biannual assessments. 
UW study staff will initiate a contact protocol approximately seven days before the time point 
date. For example, outreach for the 3 month assessment for a participant who presented to the 
ED on May 1st (05/01) will begin on July 25th – seven days before August 1st (08/01). The 
protocol will be conducted over the course of approximately 3 weeks. This protocol will include a 
combination of phone, mail, and email as determined by the contact information provided by the 


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participant. If the contact protocol is exhausted and the assessment has not been completed, 
the participant’s research coordinator will be notified. They will review the EMR and provide any 
site-specific or EMR-specific updates that may be helpful; for example, an updated telephone 
number. Additional contact attempts (calls, emails, texts, etc) will be scheduled. These contact 
attemptswill be made at varying times of the day in an effort to reach the patient (e.g., morning, 
mid-day, after business hours) and may be made by either the UW staff or the site staff. If the 
assessment is still not completed, it will be considered missed and attempts to contact the 
participant will resume as per contact protocol at the next assessment time point.   
5.2.6 Optional Extended Follow-up Assessments (36, 48, and 60 months) 
 At regular intervals through 60 months, the following will be assessed using phone, mail, or 
web-based surveys: 
1. Complications, signs and symptoms related to appendicitis and related healthcare 
utilization, time spent in healthcare, out of pocket expenses;  
2. EQ-5D20 and 10-PROMIS21; and 
3. GIQLI22. 
UW study staff will contact the participant to complete the annual assessments. Outreach will be 
conducted over the course of approximately 3 weeks and will include a combination of phone, 
mail, and email as determined by the contact information provided by the participant. If the 
contact protocol is exhausted and the assessment is not completed, additional phone calls will 
be scheduled. If the assessment is still not completed, it will be considered missed and attempts 
to contact the participant will resume as per contact protocol at the next assessment time point.   
5.2.7 Participant Burnout and Optimizing Data Collection  
Participants may experience research assessment burnout due to the frequency and number of 
questions asked of them. To optimize complete data collection, research personnel should 
recognize a participant’s reluctance to complete the research assessment and request that the 
participant instead complete a sub-set of survey responses (minimal research assessment). In 
the event that a participant prefers to complete a minimal research assessment, research 
personnel should prioritize asking the research participant questions related to signs and 
symptoms of appendicitis and aim to complete the EQ-5D survey. Study staff will be provided 
with a prioritization model to clarify what questions are high versus medium priority. The RC 
should use their best judgment to determine how many additional survey questions should be 
asked. It is preferred to miss some responses at one research assessment time point rather 
than risk the participant withdrawing altogether due to research assessment burnout. 
5.3 Medical Record Review 
Time points 
Patients consenting to the study will have their EMR reviewed at (1) pre-determined time points 
and (2) ad-hoc time points if triggered by a survey response. RCs will conduct an EMR review to 
assess the following: 


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1. Complications for patients using the National Surgical Quality Improvement Program 
(NSQIP) definitions and protocol as well as those complications related to antibiotic use; 
and 
2. Healthcare utilization events since index hospital discharge. Details of all healthcare 
utilization events related to appendicitis will include the following information: 
a. Length of stay; 
b. Use and results of repeat imaging; and 
c. Surgery type, if applicable. 
 
The 3 cohorts will undergo pre-determined review at the following time points: 
 
Randomized & Observational 
Cohorts 
EMR Only Cohort 
Index Visit 
X 
X 
Week 1 
X 
 
Week 2 
X 
 
Week 4 
X 
X 
Year 1 
X 
 
Year 2 
X 
X 
 
As needed, ad-hoc chart review will be conducted if a patient reports an adverse event and 
further documentation is needed. 
 
When possible, participants will continue to have their EMR reviewed at Year 3, Year 4, and 
Year 5. 
Data Collection 
Data is collected using the following forms: 
Form 
Description 
Form Information 
Captures information about when the form was filled out (time point), and 
by whom 
ED Visit Form 
Captures information about the hospital visit (demographics, 
admit/discharge times, symptoms) 
Imaging Form 
If patient had imaging done at any time point, captures information about 
the radiology tests and their findings 
Laboratory Results Form 
If patient had lab work done at any time point, captures information about 
the lab tests and their results 
Index Visit Treatment Form 
Filled out at the index visit only, captures information about randomization 
and/or cohort designation 
Appendectomy Form 
If patient had an appendectomy at any time point, captures information 
about the surgical procedure and treatment decision-making 
Pathology Form 
If patient had an appendectomy at any time point, captures information 
about the pathology results 
Antibiotics Form 
If patient was treated with antibiotics, captures information about the 
antibiotic treatment (both inpatient and at discharge) 
Adverse Events Form 
Captures information about adverse events at any time point 
Discharge Form 
Captures information about discharge status at any time point 


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Follow-Up Form 
For scheduled EMR reviews, captures information about the review period 
including follow-up appointments, additional visits to the ER, etc. 
 
5.4 Research Coordinator Call Triggers and Clinical Contact 
If the patient develops concerning signs or symptoms, the designated site clinician and relevant 
study team members will be informed and will follow-up with the patient directly. Clinician 
education will include recommended usual care activities in response to call triggers. 
5.4.1 Early Call Triggers (Up to 3 Months) 
The research coordinator will alert the designated site clinician and appropriate study team 
members when a patient reports to the coordinator any of the following symptoms: 
1. Persistent fevers or chills; 
2. Persistent vomiting and/or inability to take medication; 
3. Worsening abdominal pain despite pain medication; 
4. Patient requesting discussion with medical team; and 
5. Clinical concern by research coordinator (e.g., significant persistent dizziness or 
significant new diarrhea). 
The designated site clinician and study team will be responsible for determining if further 
evaluation is needed and for coordinating the patient’s care upon receiving notification from the 
research coordinator. The research coordinator will document contact with the study team by 
either 1) responding to the Survey Response Review report on the CODA portal if report of the 
call trigger was in response to a triggered surveyed question or 2) documenting by way of an 
internal study team call trigger tracking system concerns that are spontaneously reported.  
The site RC will be responsible for initiating the Serious Adverse Event (SAE) reporting process 
if the reported patient concern is an SAE. See Section 9.0. 
5.4.2 Late Call Triggers (Beyond 3 Months) 
Despite a requirement that all patients enrolled in the study have diagnostic imaging of the 
abdomen to exclude the possibility of a cancer, it is still possible that patients treated with 
antibiotics only may harbor an appendiceal mass. The research coordinator will alert the 
designated site clinician and study team if any of the following are reported any time after three 
months:  
1. Complaints of signs and symptoms of recurrent appendicitis; 
2. Unintentional weight loss of more than 15lbs; or 
3. Diagnostic imaging consistent with appendiceal mass. 
If the patient has not seen a healthcare provider to address these issues, the research 
coordinator will offer to connect the patient to the appropriate scheduling coordinator to make an 
appointment for follow-up at any of the clinical sites or the lead of the CCC.  
As noted in Section 5.4.1, the research coordinator will document contacting the study team by 
either 1) responding to the Survey Response Review report on the CODA portal if report of the 


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call trigger was in response to a triggered surveyed question or 2) documenting by way of an 
internal study team call trigger tracking system concerns that are spontaneously reported.  
Additionally, the site RC will be responsible for initiating the SAE reporting process if the 
reported patient concern is an SAE. See Section 9.0. 
5.4.3 Clinician Education 
Clinicians will be advised to follow usual clinical care pathways and principles in responding to 
these call triggers described in Sections 5.4.1 and 5.4.2. Additionally, site clinical leads will be 
formally educated through training sessions on the following study materials: protocol, research 
coordinator call triggers, and SAE reporting process.  
Clinicians will be encouraged to apply usual clinical care and potentially, repeat diagnostic 
imaging or colonoscopy for participants who did not have an appendectomy and have persistent 
gastrointestinal symptoms at or after one-year.  
5.5 Reasons for Withdrawal 
Participants may be withdrawn from the study for the following reasons: 
1. Participant desires withdrawal (reasons for withdrawal will be recorded); and 
2. Study investigator(s) deems it in the participant’s best interest to be withdrawn (reason 
for withdrawal recorded). 
5.5.1 Handling of Withdrawals 
If the participant requests to be withdrawn from the study, they will be given appropriate 
treatment, but will not continue with scheduled study follow-ups. If the participant withdraws 
from the study and withdraws consent for disclosure of future information, no further evaluations 
will be performed and additional data will not be collected. The investigators may retain and 
continue to use data collected before withdrawal of consent.  
5.6 Compensation 
5.6.1 Participant Compensation 
Participants will be paid up to $155 for completing the research assessments described in Table 
2 (Section 5.0). Payment will be provided on a pro-rated, weighted fashion: $20 for the Baseline 
Assessment, $10 for the Week 1 and 2 Assessments ($20), $20 for the Week 4 Assessment, 
$10 for Quarterly Assessments through 12 months ($40, Months 3, 6, 9, 12), $10 for the 18-
month Assessment, and $15 for the 24-month Assessment. Extended follow-up surveys at 36, 
48, and 60 months will also be pro-rated at $10 per survey. Compensation will be distributed to 
participants centrally by UW research staff unless other arrangements have been made.  
5.6.2 Site and Site Lead Compensation 
Each site will determine how best to allocate their funds to support this research at their 
hospital. Funds may be used to support study staff including site surgical and ED lead 
investigators, relevant clinical and research support staff, and research study supplies. Funds 


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for research participant compensation will not come directly from these site payments but rather 
provided by UW centrally as described in Section 5.6.1.  
5.7 Retention Activities 
5.7.1 Maintaining Contact 
Participants will be asked to confirm their contact information before beginning each research 
assessment. They will also be asked to confirm the contact information of family members, 
friends, and employers who may be asked to update the participant’s contact information should 
they be otherwise lost to follow-up. Participants may receive personalized birthday cards with 
$5.00 coffee-shop gift card or other small incentive annually during their birthday month. 
5.7.2 Contact between Assessments 
Three interim communications will be performed between 12 and 24 month follow-up 
assessments to help retain participants in the study and to improve communication with them. 
During the year, coordinators will: 
1. Send a thank-you “mailer” to the participant in recognition of his or her participation. The 
mailer may include an updated site newsletter and a small token of appreciation, such as 
a pen with the study logo; 
2. Request an update in contact information; and 
3. May send a birthday card with a $5 gift card or another small incentive. 
6.0 Outcome Assessments  
6.1 Primary Outcome  
Patient Reported Outcomes (PROs) will be assessed for adults using both generic and disease-
specific surveys utilizing the QoL instruments in Table 4. 
Table 4. PRO Measures. 
Validated 
Scale 
Description 
EQ-5D20 
A preference-based instrument designed to measure generic health status across 5 dimensions 
of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, with 
3 response levels (i.e., no problems, some problems, extreme problems). A Visual Analog 
Scale (scored 0-100) is also included. 
10 PROMIS 
Global Health 
Short Form21 
A 10-item instrument measuring domains that can be scored into a Global Physical Health 
component and Global Mental Health component. Each item includes 5 response choices, with 
the exception of the common 11–point pain intensity item ("How would you rate your pain on 
average?" with 0=no pain and 10=worst imaginable pain). 
Decision 
Regret Scale23 
A 5-item validated questionnaire that measures regret among patients following a specific 
treatment decision. Scores range from 0-100 and higher scores reflect higher levels of regret. 
While developed for use in patients undergoing treatment for cancer, the questions are general 
in nature and adaptable to diverse clinical experiences. 
GIQLI22 
A 36-item questionnaire assessing 5 domains: GI symptoms, physical function, emotional well-
being, social well-being and perception of medical treatment measured by a single item 
question. Each item has 5 response choices (i.e., all of the time, most of the time, some of the 
time, a little of the time, never). In addition, the measure produces and overall QoLscore (0-144) 
where higher numbers indicate greater QoL. 


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6.2 Secondary Outcomes 
6.2.1 Clinical Complications 
Death, SAEs, and complications (reported as AEs via EMR review) will be assessed and 
recorded through the study surveillance period. Complications (reported as AEs) will incorporate 
NSQIP standards and definitions as well as events related to antibiotic-related complications.  
 
Serious Adverse Events 
 
Adverse event 
Death 
 
 
Life-threatening event 
 
Severe antibiotic reaction 
Mild/moderate antibiotic reaction 
CVA or stroke 
 
MI requiring treatment or cardiac arrest 
Myocardial infarction 
Atrial arrhythmia 
Unplanned admit to ICU 
 
Acute Renal Failure (requiring dialysis) 
Major UTI (e.g., pyelonephritis) 
Urinary retention 
Acute Renal Failure (no dialysis) 
Progressive renal insufficiency 
C. difficile colitis (requiring colon resection) 
 
Pulmonary embolism requiring therapy 
DVT/PE requiring treatment 
Coma >24 hours 
 
Septic shock (requiring pressors) 
Sepsis 
 
Serious Adverse Events (continued) 
 
Adverse event (continued) 
Bleeding requiring transfusion 
 
Newly infected prosthetic graft infection 
(such as a cardiac valve that gets infected or 
synthetic bypass graft infection secondary to 
appendicitis) 
 
Mechanical ventilation >48 hours 
Tracheal reintubation/tracheostomy 
Colostomy or ileostomy 
NG tube replacement (non-routine) 
Bowel obstruction 
Ileus 
 
Organ/space infection (including peritonitis) 
Surgical site infection 
Intra-ab Abscess 
Severe dehydration 
Hernia 
Malignant hyperthermia 
Pneumonia 
Other infection 
Other post-op occurrence: unspecified 
Other non-operative intervention: unspecified 
Unplanned (re)operative intervention during index 
C. difficile colitis (not requiring colon resect) 
Other life threatening event 
 
 
Rehospitalization (other than for txt of 
appendicitis) 
 


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Monitored event 
 
Appendiceal cancer 
 
Perforation 
 
Length of stay postoperatively 
 
6.2.2 Eventual Appendectomy 
Participants will be asked whether they have had an appendectomy at each contact through 
their four-week follow-up after the index diagnosis of appendicitis, and then surveyed at regular 
intervals to determine if they developed recurrent appendicitis and the resulting treatment (non-
operative intervention, unplanned re-operative intervention, planned or elective appendectomy). 
With the participant’s informed consent, the research coordinator will obtain all inpatient and 
outpatient medical records related to AEs or recurrent appendicitis and records will be 
abstracted to determine whether the AEs were associated with the incident appendicitis or 
whether recurrent appendicitis was confirmed. If recurrent appendicitis was confirmed, 
treatment and patient/clinician decision-making will be recorded on the EMR form. 
Patients reporting eventual appendectomy will be surveyed to determine, from the patient 
perspective, the reason for eventual appendectomy. 
7.0 Data Management and Information Security 
7.1 Data Management 
Data management will be the responsibility of the site investigators for data collected at their 
particular site, and the UW DCC for the combined data from all sites.   
At sites, all study questionnaires completed in person or by phone (or by mail or email) will be 
reviewed by research coordinators for accuracy and completeness. Through the Week 2 follow-
up and as needed subsequently through the 2-year follow-up, data collection is the 
responsibility of the study staff at the site under the supervision of the site investigator. During 
the study, the site investigator will maintain complete and accurate documentation for the study. 
The UW DCC will provide support for data management, quality review, analysis, and reporting 
of the study data. The DCC will create the electronic study database using REDCap (Research 
Electronic Data Capture). REDCap is a secure web application for building and managing online 
surveys and databases.   
Patient follow-up from 4-weeks on will be completed using customizable software from DatStat, 
Inc (Seattle, WA) to securely manage survey distribution methods, response data collection, 
and reporting. UW study staff will complete data audits to ensure data quality as well as 
accurate data-entry for surveys received by mail.  
7.1.2 Data Quality Monitoring  
The CCC and DCC will review participant enrollment, reasons for exclusion, 
participant demographics, and follow-up rates by site in order to assess proximity to enrollment 
targets, site performance, and protocol adherence.   
In addition, the DCC will perform early quality assurance checks by running REDCap 
Data Quality reports. These reports include missing values for required fields, incorrect data 


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type, range checks, outliers, hidden fields that contain values, and multiple choice fields with 
invalid values. Values that need to be corrected will be brought to the attention of the research 
staff at that site.  
7.2 Information Security 
Sites: 
All participant data collected on paper at sites will be stored in locked file cabinets located in the 
site research offices.  
All data entered onto laptop/desktop computers located at sites will be secured via each site’s 
Information Security infrastructure.  Information Security at all participating sites is multi-layered 
and includes physical security measures, network security measures, managed servers, and 
desktop/laptop computers with authentication and authorization controls. All systems are 
designed and implemented to properly secure restricted or confidential information, including 
PHI, from inadvertent or unauthorized disclosure. All policies and procedures adhere to federal, 
state, and health system requirements. Servers, desktops, and laptops are under active 
management by an Integrated Technology Services Group (ITSG) at each participating site. In 
addition to maintaining anti-virus and firewall installations, the ITSG audits patch status of 
systems connected to the network and installs any missing updates or patches found. Servers 
have defined change control periods for operating system maintenance but are patched or 
updated outside the schedule as necessary to address threats. Anti-virus software is configured 
to update daily. The host-based firewalls restrict inbound connections to only the subnets where 
department workforce resides or that are needed for firewall administration. The firewall rule set 
on the dedicated server is further restricted to the network subnets. A specific Windows domain 
account is required to access computers. Domain passwords must be at least 8 characters in 
length, conform to complexity rules, and be changed at least every 120 days. Database systems 
and security policies are established and overseen by administrative staff members who do not 
require research funding. 
 
RedCAP: 
All data, including PHI, names, and contact information will be entered onto a HIPAA and 21 
CFR Part 11- compliant database. Participant PHI, including names, contact information, health 
information, will be entered onto this database. Only study staff will have access to the database 
and each study staff member will be given separate access only after completing study-required 
trainings.   
 
DatStat: 
Data Transmission and Storage 
DatStat servers, databases, and web presences employ multiple forms of security features, 
while security protocols are designed to protect both the data itself, as well as the participants 
involved in data collection efforts. 
DatStat secure servers are registered with site certificates provided by AddTrust that provide for 
advanced encryption over the wire. As each user moves through the survey form, his/her 
responses are encrypted while in-transit between the browser and DatStat's server using SSL 
(Secure Sockets Layer) and 40, 56, or 128-bit Public Key Encryption.  


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All servers used for data collection are highly fault-tolerant and equipped with redundant, hot-
pluggable power supplies, redundant network interfaces, and RAID 5 hot-swappable disk 
storage. All primary servers are plugged into a monitored, uninterruptible power supply (UPS).  
Physical security 
 
DatStat servers are stored in a locked server cabinet/rack, which are housed in a state-of-the-
art, well-ventilated data center. Physical access to servers and data backup is restricted to a 
minimal number of IT professionals. The facility is secured by guards who monitor all access to 
the building and will notify DatStat personnel of any building compromise or intrusion. 
Logical security 
In addition to the physical safeguards listed above, the data center is monitored 24/7 by 
Information Technology (IT) and security staff via equipment monitoring and Closed-Circuit 
Television. Servers are protected from remote attacks through use of dedicated hardware 
firewalls (Watchguard), with auditing enabled at the recommended settings. Watchguard 
LiveSecurity keeps IT staff advised of all known security alerts. Firewalls closely monitor traffic 
to block suspicious packets from access to all systems. 
Security patches are applied to DatStat servers on a timely and ongoing basis. Logs are created 
by the web servers to increase accountability and are essential in investigating incidents after 
the fact. The following are logged: failed and successful logins, attempts to access files/ 
directories without authority, successful and failed attempts to access sensitive data. 
8.0 Statistical Analysis Plan and Stopping Rules  
8.1 Randomization Overview 
This is a non-inferiority based, pragmatic, randomized controlled trial (RCT) of antibiotics versus 
appendectomy for the treatment of uncomplicated appendicitis with a concurrent observational 
cohort to characterize any selection bias associated with patients choosing to participate in the 
randomized trial, and to support the generalizability of study results. By necessity, this is an un-
blinded study (patients will know if they were randomized to appendectomy or antibiotics), and 
analysts will know the treatment allocation of study participants. The DCC will generate and 
maintain randomization lists for each practice site. We will use block randomization within 
practice sites, with random blocks of 4, 6, or 8 participants. Using block randomization ensures 
that equal numbers of participants are randomized to the intervention and control arm and that 
the two groups are balanced at periodic enrollment intervals. Crossover, in the conventional 
manner, is defined as a patient who is randomized to appendectomy who refuses to undergo 
surgery or someone who is randomized to antibiotics but chooses appendectomy before the 
antibiotics are started. For the sake of convenience in describing statistical analysis and data 
monitoring plans, we define the term early antibiotics failures (or treatment changed) as 
patients in the antibiotics treatment arm who were treated with appendectomy within four weeks 
after randomization. 
8.2 Outcomes Measures  
The primary analysis outcome is the EQ-5D at four weeks following randomization to treatment 
in the intention-to-treat (ITT) population. Important clinical endpoints include the following: 
complications or AEs associated with antibiotics or appendectomy; days until resolution of 
symptoms; rates of perforated appendicitis; rates of appendiceal cancer; hospital days; number 
of days using antibiotics beyond the initial treatment schedule; clinic visits; and caregiver/patient 


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“time in healthcare.” Additional PRO measures include the 10 PROMIS Global Health Short 
Form, the Decision Regret Scale, and GIQLI. 
8.3 General Analytic Strategy  
The primary evaluation of EQ-5D at four-weeks will be conducted using an ITT analysis, where 
patients’ data are analyzed according to the patients’ randomized treatment assignment. Using 
this analytic approach in a non-inferiority study design comparing antibiotics treatment to 
appendectomy, we aim to test whether the global EQ-5D scores are not different by more than a 
margin of 5% (M = 5%). The margin (5%) was selected because it is within the meaningful 
clinical important difference (MCID) threshold of the EQ-5D, which is 5-10%.20,24,25 
1. Primary Analysis, Aim 1 – Patient-reported QoL, as measured by the EQ-5D at four-
weeks, will be assessed using a linear regression model that adjusts for an indicator of 
randomized treatment group assignment and for all factors used to stratify randomization 
(e.g., practice site). As recommended by the United States Food and Drug 
Administration guidelines on clinical trial design,26 the estimated treatment effect and 
97.5% one-sided confidence interval (CI) will be compared to the non-inferiority margin 
(M = -5%).27-29 We will conclude that antibiotics are non-inferior to appendectomy when 
the entire 97.5% one-sided confidence interval is greater than M (Figure 1, example trial 
conclusion A). This is equivalent to a one-sided (α=0.025) test of the null hypothesis 
H0: Δ < -5%, where Δ represents the difference in mean EQ-5D at four-weeks comparing 
the antibiotics treatment strategy to the appendectomy treatment strategy. If the null 
hypothesis of H0: Δ < -5% is rejected at the final evaluation, we will conduct a test of 
superiority to determine the level of statistical evidence supporting an alternative 
hypothesis HA: Δ > 0% (Figure 1, example trial conclusion B). For Sub Aim 1, we will 
similarly evaluate non-inferiority on patient-reported QoL among the cohort without 
appendicolith.  
 
Figure 1. Example Trial Conclusions in a Non-inferiority Trial. 
2. Secondary Analysis, Aim 1 – Secondary analyses of the primary outcome measures will 
include examining the entire trajectory of EQ-5D QoL measurements for each patient 
using linear mixed effects models for longitudinal data.30 While patient-elected changes 
in treatment and early antibiotics failures are anticipated, the ITT approach is an 
appropriate primary analysis. We will conduct a secondary as-treated analysis of the 
primary outcome measure that appropriately accounts for patient- or provider-level 
characteristics found to be differentially represented among patients in the antibiotics 


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arm who are treated with appendectomy and those in the appendectomy arm who do not 
ultimately have surgery. Careful as-treated and secondary data analyses are of 
importance in understanding the effectiveness of the treatments and in assessing in 
which subgroups is the antibiotics treatment strategy most effective.31 A simple as-
treated analysis is problematic because randomization is broken when select patients in 
the antibiotics arm ultimately receive appendectomy or surgery-assigned participants 
who later choose to forego surgery. Thus, patients who are successfully treated with 
antibiotics and do not undergo appendectomy may differ demographically or clinically in 
ways that introduce bias in a naive as-treated analysis. Detry (JAMA 2014) recommends 
both an ITT and a careful as-treated analysis to address treatment changes in non-
inferiority trials where non-adherence, crossover, or treatment changes are present. If 
we find a difference between the ITT and as-treated results, the ITT results will be 
considered the primary analysis.32 
We will consider a two-stage approach for this as-treated analysis to: 1) identify 
subgroups that are likely to require appendectomy, therefore, should not be considered 
as good candidates for treatment with antibiotics, and 2) estimate the complier average 
causal effect (CACE), which seeks to compare the outcomes of patients treated 
successfully in the antibiotics arm (i.e., did not ultimately have surgery) with patients 
randomized to the appendectomy arm who similarly would not have crossed over had 
they been randomized to the antibiotics arm. The CACE framework considers the ITT 
mean in each randomized arm as being comprised of two subgroup means: 1) patients 
who would be successfully treated with antibiotics without appendectomy and 2) patients 
who would eventually require appendectomy after being treated with antibiotics. We are 
able to directly observe which patients in the antibiotics arm ultimately cross over, but 
require the CACE framework to identify similar patients in the appendectomy arm. We 
will use a maximum likelihood mixture modeling approach to identify the optimal 
comparison group from the control arm for observed compliers in the intervention arm.33 
This application of mixture modeling permits an examination of two aspects of 
intervention process, the prediction of early antibiotics failures in the appendectomy 
group and the examination the treatment effect on QoL among patients who are suitable 
candidates for treatment with antibiotics.34,35 
We will also compare secondary PROs (i.e., 10 PROMIS Global Health Short Form, 
GIQLI, and the Decision Regret Scale) using an ITT framework and linear regression 
models. Similar to the primary outcome measure, secondary PROs will be assessed 
using model-based point estimates and associated confidence intervals. The magnitude 
of effect will be judged a posteriori using margins that are of comparable magnitude as 
the EQ-5D in terms of the Cohen’s d statistic. In an exploratory analysis, the complete 
longitudinal trajectory of all PRO metrics will be assessed with linear mixed effects 
models. 
3. Exploratory Aim A – Using only data from patients enrolled in the antibiotics arm, we 
will also examine the association of these characteristics with eventual appendectomy. 
We will employ univariate logistic regression models to identify and characterize 
associations with unplanned appendectomy. If we find that a number of baseline 
characteristics are relevant and the rate of unplanned appendectomy is high enough 
(e.g., >10-15%), we will use multivariable analyses to compare these characteristics 
among those undergoing early appendectomy (defined within the first four weeks) and 
eventual appendectomy (after four weeks). Due to the potentially large number of input 
variables, interactions, and longitudinal assessments, we will also use modern model 


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development methods such as the least absolute shrinkage and selection operator 
(LASSO) with boosting.36,37 Boosting provides a more sophisticated approach towards 
building multivariable predictive models and allows nonlinear relationships between the 
input variables and risk of requiring appendectomy after first being treated with 
antibiotics. Boosting is a multiple prediction and aggregation method for classification, 
where a “base learner” fitting method is fitted multiple times on reweighted data and a 
final estimator is constructed through a linear combination of the multiple estimates. 
Results of these analyses will be considered hypothesis generating and may support 
secondary studies aimed at predictive modeling. 
4. Primary Analysis, Aim 2 – Clinical endpoints (e.g., days until resolution of symptoms; 
rates of perforated appendicitis; extent of operation and surgical complications; 
complications associated with antibiotics; hospital days; number of days using antibiotics 
beyond the initial treatment; clinic visits; and caregiver/patient “time in healthcare”) will 
also be compared between ITT groups using regression models appropriate to each 
endpoint (e.g., linear, logistic, Poisson, or Cox proportional hazards regression models), 
along with a similar non-inferiority framework with margins based on MCIDs. For Sub 
Aim 2 we will similarly compare clinical endpoints among the cohort without 
appendicolith. 
5. Exploratory Aim B – One assumption is that patients included in the RCT are sufficiently 
similar to those from the general population of patients with appendicitis. Using simple 
univariate descriptive and comparative statistics (e.g., t-tests, Chi-squared tests), we will 
compare randomized patients to those in the parallel observational cohort to identify 
selection bias. We will also compare the primary outcome measures between 
randomized and non-randomized patients by examining the entire trajectory of EQ-5D 
QoL measurements using linear mixed effects models for longitudinal data, providing an 
assessment of differences in the rate of change of QoL. We will adjust for patient- or 
provider-level characteristics found to be differentially represented in RCT. Using 
methods similar to those described in the plan for Aim 1 Secondary Analyses, we will 
adjust for treatment received to fully assess whether patients who participate in the RCT 
have a different outcome trajectory than patients in the observational cohort. 
8.4 Missing Data  
We will conduct a missing data analysis to describe and characterize enrolled participants who 
do not provide data due to attrition. As described by Molenberghs and Kenward (2007), we will 
use inverse probability weighting in secondary analysis within each longitudinal regression 
model to inflate the weights of cases that are under-represented in the analysis due to selective 
attrition and/or non-participation.38 We will also conduct sensitivity analyses using 10-fold 
multiple imputation to assess the robustness of the results when missing data are imputed. We 
will assess the sensitivity of inferences made from missing data first by using the two previously 
described methods for dealing with missing data and second, by imputing missing data under 
both pessimistic and optimistic scenarios to provide bounds on the statistical uncertainty. The 
characteristics of non-responders will be summarized in our final report and we will present the 
sensitivity of the estimated treatment effect due to alternative missing data methods. 
8.5 Sample Size and Statistical Power  
Prior studies suggest that non-clinical outcomes (e.g., loss of time from work and pain scores) 
were similar between groups, but did not evaluate a global QoL measure. The EQ-5D QoL 


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index ranges from 0 (worst QoL) to 1 (highest QoL), where anchor-based methods have shown 
that the MCID ranges 5%-10%. Based on data from a prior study of appendectomy with EQ-5D 
scores at 12 weeks, we estimate that the mean EQ-5D for appendectomy patients will be 0.90 
with a standard deviation of 0.12. In order to assess QoL differences between interventions, we 
will recruit a total of 1552 patients assuming a 90% follow-up at four-weeks. This gives the study 
high power (>99%) to rule out EQ-5D differences between-groups as small as 5% (e.g., if we 
observe treatment differences of 0 to 2%) and 80% power if we observe a treatment difference 
of 3% (Table 5, below). 
Previous Washington State evaluations of patients undergoing appendectomy (Table 1), 
identified that 2-3% of the population is African American, 10-12% Hispanic, 10-15% are 
Medicaid beneficiaries, and 10% will be above 64 years of age. Recruiting 1552 total patients 
will allow for a subgroup evaluation based on older age and Medicaid beneficiary status. 
Assuming 50% recruitment of these populations we anticipate including ~500 Medicaid 
beneficiaries and ~450 patients ≥65 years. As demonstrated in Table 5, this study also has 
adequate power (>80%) to rule out differences of 5% for observed treatment effect of Δ=0% 
within subgroups as small as n=250 patients, or treatment differences of Δ=-1% within 
subgroups of at least n=400. For this reason, we expect the study will be able to assess these 
two subgroups. All other subgroup evaluations will be post hoc and used for hypothesis 
development only.  
Table 5. Statistical Power to Declare Non-inferiority on Patient-reported QoL, Overall and by 
Subgroup (Non-inferiority Margin, M = -5%, one-sided α=0.025). 
Treatment Difference, Δ 
Overall  
Subgroups 
N=1552 
N=250 
N=400 
N=500 
-3% 
82.6% 
- 
- 
- 
-2% 
99.4% 
- 
57.1% 
67.9% 
-1% 
100% 
62.4% 
83.8% 
91.4% 
0% 
100% 
83.0% 
96.4% 
98.8% 
8.6 Data and Safety Monitoring Plan (DSMP) 
An independent DSMB will be created to review the accruing data to: 1) ensure that study 
conduct, enrollment, and patient follow-up is adequate; 2) ensure that there are no serious 
safety concerns; and 3) assess evidence related to patient-reported QoL. The DSMB will be 
enlisted by the DCC in consultation with the executive committee. 
The primary objective for interim analyses is to allow careful and continuing analysis of safety 
outcomes by randomization group. We will record and present all SAEs that occur during follow-
up, but focus interim monitoring for those events that occur within the first four weeks of follow-
up (since this is the time period in which the major treatment related events would be expected). 
The DSMB will review safety and efficacy data reports every six months and will conduct formal 
interim analyses for efficacy and safety once enrollment in the randomized cohort meets targets 
of 400 and 800-1000 participants. We anticipate these targets will align with analysis occurring 
at 18 and 30 months following enrollment. If recruitment in the study is slower than expected, 
the DSMB will be encouraged to consider as a contingency that investigators continue to recruit 
patients for up to 4.5 years with the goal of accomplishing the Aim 1 analysis (four-weeks) in all, 
acknowledging that longer term outcomes will only be assessed in a subset of patients. At 
sample sizes considerably smaller than that projected (Table 5), the study will have sufficient 
power to address Aim 1, excluding the non-inferiority margin when large differences in EQ-5D 
are observed (e.g., 3%). 


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1. Safety Monitoring – We will perform interim analyses of accruing safety data. SAEs 
(described in section 9.1) will be monitored throughout the course of the study. The 
DSMB will review tabulated SAEs by treatment group every six months; however, all 
deaths will be reported to the DSMB immediately. With additional guidance from the 
DSMB, we propose to monitor and compare three safety endpoints between 
randomization groups: 1) per-patient indicator of “any” SAE, 2) per-patient SAE count, 
and 3) all-cause mortality. The research coordinators at each practice site will monitor 
participants for, or be alerted by UW study staff regarding the presence of, SAEs and 
AEs during inpatient stays using EMR. This process includes reviews of SAEs and AEs 
that occur at other hospitals not included in the study, with details obtained through 
requested records from those hospitalizations. An adjudication process related to these 
events will be led by a clinician not otherwise involved in the trial. This independent 
safety monitor (ISM) will review SAE forms for data quality control. SAE forms needing 
additional specification will be returned to the site PI for completion prior to finalization. 
All SAEs will also be adjudicated by the surgical site lead.  
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.  
2. 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 


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antibiotic failure overall, and in a priori selected subgroups (e.g., older patients and 
Medicaid beneficiaries), as well as other important clinical endpoints. 
3. 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.  
4. 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 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. 
5. Revisions – These monitoring guidelines may be revised at the discretion and 
recommendation of the DSMB. 
6. 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. 
6. Shell DSMB report tables are located in Appendix A. 
 
9.0 Study Related SAEs 
9.1 Identification of SAEs 
Participants in the randomization and observational cohorts will be monitored for SAEs 
throughout their study surveillance period (enrollment through the optional extended follow-up). 
The occurrence of an SAE may come to the attention of study personnel during study follow-up 


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phone interview, by UW study staff personnel conducting follow-up, or by a study participant 
calling the study team or presenting for medical care. If an SAE comes to the attention of study 
personnel via patient or family report, the site research coordinator will be notified that an SAE 
form needs to be completed. The site research coordinator will then use the EMR to fill out the 
SAE form. The site PI will then complete the form and sign the form. The SAE form will then be 
submitted to the DCC who will provide it to the ISM. The ISM will review the SAE form and ask 
the surgical site lead for additional clarification or specification as he/she sees necessary. SAE 
forms for events other than death will be summarized for the DSMB every 6 months; however, 
deaths due to any cause will be reported to the DSMB immediately. 
9.2 SAE Reporting 
Life-threatening complications or SAEs are a very rare possibility with surgical treatment and 
even less likely with antibiotic treatment. SAEs are defined as one of the following conditions 
(also listed in section 6.2.1): 
1. Death during the period of protocol-defined surveillance; 
2. Life-threatening event related to the treatment or significant disability/incapacity related 
to the treatment; or  
3. Inpatient hospitalization (other than for treatment of recurrent appendicitis). 
 
All SAEs will be: 
1. Recorded on the appropriate SAE case report form; 
2. Adjudicated by the ISM; 
3. Reviewed and evaluated by the DSMB;  
4. Followed until satisfactory resolution or until the study investigators deem the event to be 
chronic or the participant to be stable;  
5. Reported to the study investigators, the project managers, and site IRBs per their 
reporting guidelines; and 
6. The study investigators will also report SAEs to PCORI in its role as funder. 
9.3 Assignment of SAEs as Treatment Related 
The determination of whether an SAE is related to the treatment will be assessed by the ISM 
and surgical site lead, based on supporting documentation provided by the research 
coordinators case reports or in consultation with the treating physician, as needed.  
10.0 Reporting Procedures 
SAEs will be captured on the appropriate source document. Information to be collected includes 
event description, date event occurred, date study personnel became aware of the event, 
investigator assessment of event severity, event outcome, and relationship to study treatment. 
All SAEs will also have information on action taken at time of report, date SAE resolved, 
outcome at time of SAE report, and, depending on the site, whether the IRB has been notified.  
For SAEs, the date of resolution (or when the event is deemed stable/chronic) will be noted on 
the appropriate case report form.  


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11.0 Quality and Performance Management Plans 
11.1 Quality Management Plan  
A quality management plan (QMP) will be created to ensure early identification and resolution of 
problems or concerns related to the study. The QMP will include verification that sites have 
appropriately met the requirements to assure quality of all study-related activities. Each site will 
be responsible for maintaining accurate and complete patient charts and informed consent 
documentation. The QMP is in place to verify good practice. Research staff from the CCC will 
be responsible for the following activities in coordination with collaborating sites to verify QMP 
requirements are met: 
1. Site Initiation Visit. This will involve review of: 
i. Regulatory approval documents; 
ii. Human subjects training documentation for all study staff; 
iii. Documentation of study-related required trainings; and  
iv. HIPAA-compliant storage plans for participant data (electronic and paper-
based) 
2. Site audit 6 months after study enrollment initiation. This will involve: 
i. Select chart audits;  
ii. Select audit of informed consent form documentation; and  
iii. Review of Protocol Violations and Deviations.  
3. Annual Site Monitoring Visits (at a minimum) to review/complete: 
i. Regulatory approval documents; 
ii. Select chart audits; 
iii. Select audit of informed consent form documentation;  
iv. Review of Protocol Violations and Deviations. and 
v. Review of staff training logs. 
4. The DCC will set up data quality checks within the data entry system which will 
check for appropriate and on-time data entry within relevant protocol-defined time 
windows, missing information, inconsistencies and logic errors. The DCC will 
monitor this information on a regular basis.  
For sites that are found to have several inconsistencies and errors in data quality and 
completeness, or an increased number of protocol deviations compared to other sites, more 
monitoring visits will be scheduled and conducted as needed.  
11.2 Performance Management Plan 
Site study leadership teams will review enrollment rates and any outstanding needs or concerns 
with the CCC Director and CODA Project Manager on a regular basis. The purpose of these 
individual site meetings is to monitor site progress against anticipated and expected site 
enrollment targets. To meet study enrollment milestone targets, individual sites are expected to 


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screen all appendicitis patients. If screening/recruitment goals are not being met, the CCC will 
implement the following Performance Management Plan, consisting of: 
1. Site Progress Call to review and discuss: 
i. Site specific screening and randomization rates; 
ii. Missed participants, study refusals; 
iii. Statement of work and milestones review; 
iv. Support or training needs for the site from the CCC; and 
v. Plan of action to address enrollment shortfalls 
2. Interval Check-In Call: 
i. Site specific screening and randomization rates  
ii. Plan of action results 
b. Follow-up Call(s) as needed: 
i. Continued training 
ii. In-person site visit / shadowing of study staff 
Site performance, screening rates, is monitored on a weekly basis by the CODA Executive 
Committee. If a site consistently fails to meet expectations in comparison to the average study 
site, suspension or termination of the site subcontract may be necessary.  
11.3 Protocol Violations and Deviations 
A protocol violation is any non-compliance with the clinical trial protocol or Good Clinical 
Practices. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff and most often is related to study enrollment. Anticipated protocol violations 
are 1) Participant enrolled but did not meet inclusion criteria, 2) Participant enrolled but 
exclusion criteria present or eligibility criteria not met, 3) Consent not obtained in accordance 
with IRB guidelines, 4) Randomization failure, 5) Clinical team intervention outside of the 
protocol (other than those elected by participant), 6) Participant in antibiotics arm received 
antibiotics outside of protocol during hospital stay, and 7) Participant in antibiotics arm received 
antibiotics outside of protocol at discharge. Participants enrolled and later found to be ineligible 
will still be followed. Specifically, a participant enrolled into the randomization or observational 
cohort that is later found to not have appendicitis will still be asked to complete study 
assessments. To document the participant’s ineligibility, a protocol violation will be submitted. 
Participants enrolled in the EMR cohort who are later found not to have appendicitis will be 
withdrawn from the study. As a result of violations, corrective actions will be developed by the 
site and implemented promptly. 
A protocol deviation is a smaller digression from study protocol. Deviations are monitored with 
consideration for protocol amendment should it become clear that the original protocol was too 
inflexible. The only anticipated protocol deviations are >7 hours between first administration of 
antibiotics and study approach by the research coordinator and not watching the video or 
reviewing the study pamphlet prior to study consent. Additional protocol deviations will be 
recorded and described.  
It is the responsibility of the site to use continuous vigilance to identify and report violations and 
deviations within 5 working days of identification of the protocol violation/deviation.  


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All violations and deviations from the protocol will be addressed in study participant source 
documents. A completed copy of the Protocol Violations and Deviation Form will be maintained 
in the regulatory file, as well as in the participant’s study chart. Protocol violations and 
deviations will be sent to the local IRB per their guidelines. The site investigator/study staff will 
be responsible for knowing and adhering to their IRB requirements. 
12.0 Protection of Human Participants 
We expect that most patients will have good baseline health but will not exclude patients with 
most stable and chronic medical conditions, other than those with complicated appendicitis and 
characteristics described in exclusion criteria.  
Because the proposed study population will include Spanish-speaking patients, all consent 
documents and materials will be translated to Spanish. Women of childbearing potential will be 
excluded if they have a positive pregnancy test documented prior to enrollment or anticipate 
being pregnant in the following month. Prisoners will be excluded. There is no evidence from 
prior studies to suggest there will be differences in intervention effect among sex/gender or 
racial/ethnic subgroups.  
The risks and benefits for participants enrolled in this trial are appropriately balanced. Both of 
the study interventions (appendectomy and IV antibiotics) are standard, and all of the drugs 
used in the study are currently in clinical use. Potential risks to participants include the potential 
AEs that are well described as complications of acute appendicitis, including appendiceal 
perforation, intraabdominal abscess, sepsis, pain, and loss of time from work and normal 
activities. Based on prior studies, it is not expected that these complications will be greater in 
patients assigned to the non-operative strategy group, but that is not known for certain. Patients 
assigned to the operative strategy will be participant to the well-described risks of surgery 
including adverse anesthesia reaction, perforation of viscus, wound infection, or bleeding. 
These risks would be similar to those that patients with AUA would encounter as part of 
standard care. All patients will also have potential risks of adverse reaction to antibiotics 
including allergic reaction or antibiotic-associated and Clostridium difficile colitis. Other risks 
include potential loss of patient confidentiality through the collection of study data. It is expected 
that the benefits of the study (including avoidance of surgery and its associated risks in the non-
operative group and the benefits of the knowledge gained that will improve patient choices in 
the future) justify the potential risks. 
The alternative to participation in the clinical trial is receipt of usual care, which currently most 
often involves urgent surgical appendectomy with peri-operative antibiotics. Patients will be 
informed of alternatives to participation in the informed consent process. 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of both treatment options will be provided to the participants and 
their families using standardized materials including a web-based video. Consent forms 
describing in detail the study interventions, study procedures, and risks are given to the 
participant and documentation of informed consent will be required prior to initiating treatment 
assignment if patient consents to randomization.  
Consent forms will be IRB-approved and the participant will be given sufficient time to read and 
review the document and discuss with their family member, friend, or legal representative. If 
they require assistance to reach their family member, friend, or legal representative, such as the 
use of a telephone, that will be facilitated. After this, they will be specifically asked if they have 
any questions or concerns, which will be addressed, or would like more time to consider their 


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participation, which will also be provided. The study investigator or coordinator will explain the 
research study to the participant and answer any questions that may arise. The participants will 
sign the informed consent prior to completing any study related activities, including 
randomization if the participant were to choose that participation option. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
will be given to the participants for their records. The rights and welfare of the participants will 
be protected by emphasizing to them that they will still be able to receive medical care at the 
facility if they decline to participate in this study. 
Participant confidentiality is strictly held in trust by the participating investigators and their staff.  
13.0 Ancillary Studies 
An ancillary study subcommittee within the CCC will work with interested investigators, 
representatives of PCORI and CODA stakeholders to coordinate, seek funding for, facilitate and 
plan ancillary studies that may be linked to the CODA trial. 
14.0 References 
1. Chang DC, Shiozawa A, Nguyen LL, et al. Cost of inpatient care and its association with 
hospital competition. J Am Coll Surg 2011;212:12-9.  
2. Sauerland S, Jaschinski T, Neugebauer EA. Laparoscopic versus open surgery for 
suspected appendicitis. Cochrane Database Syst Rev 2010;(10):CD001546. 
doi:CD001546.  
3. Coldrey E. Treatment of acute appendicitis. Br Med J 1956;2:1458-61.  
4. Antibiotics resurface as alternative to removing appendix 2015. Kolata G. (Accessed 
Nov. 11, 2015, at http://www.nytimes.com/2015/05/19/health/antibiotics-resurface-as-
alternative-to-removing-appendix.html?_r=0).  
5. Wojciechowicz KH, Hoffkamp HJ, van Hulst RA. Conservative treatment of acute 
appendicitis: an overview. Int Marit Health 2010;62:265-72.  
6. Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic treatment in acute 
appendicitis. a prospective multicenter randomized controlled trial. World J Surg 
2006;30:1033-7.  
7. Hansson J, Korner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical 
trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis 
in unselected patients. Br J Surg 2009;96:473-81.  
8. Eriksson S, Granstrom L. Randomized controlled trial of appendicectomy versus 
antibiotic therapy for acute appendicitis. Br J Surg 1995;82:166-9.  
9. Malik AA, Bari SU. Conservative management of acute appendicitis. J Gastrointest Surg 
2009;13:966-70.  
10. Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic acid versus appendicectomy 
for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, 
randomised controlled trial. Lancet 2011;377:1573-9.  
11. Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for 
treatment of uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA 
2015;313:2340-8.  
12. Mason RJ, Moazzez A, Sohn H, Katkhouda N. Meta-analysis of randomized trials 
comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or 
phlegmon) appendicitis. Surg Infect (Larchmt) 2012;13:74-84.  
13. McCutcheon BA, Chang DC, Marcus LP, et al. Long-term outcomes of patients with 
nonsurgically managed uncomplicated appendicitis. J Am Coll Surg 2014;218:905-13.  


Flum/Talan 
Study Protocol Version 6.1 
February 2019 
41 
 
14. Carr NJ. The pathology of acute appendicitis. Ann Diagnost Pathol 2000;4:46-58.  
15. Mason RJ. Surgery for appendicitis: is it necessary? Surg Infect (Larchmt) 2008;9:481-
8.  
16. Teixeira PG, Sivrikoz E, Inaba K, Talving P, Lam L, Demetriades D. Appendectomy 
timing: waiting until the next morning increases the risk of surgical site infections. Ann Surg 
2012;256:538-43.  
17. Eko FN, Ryb GE, Drager L, Goldwater E, Wu JJ, Counihan TC. Ideal timing of surgery 
for acute uncomplicated appendicitis. N Am J Med Sci 2013;5:22-7.  
18. Swidsinski A, Dorffel Y, Loening-Baucke V, et al. Acute appendicitis is characterised by 
local invasion with Fusobacterium nucleatum/necrophorum. Gut 2011;60:34-40.  
19. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated 
intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society 
and the Infectious Diseases Society of America. Surg Infect (Larchmt) 2010;11:79-109.  
20. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med 2001;33:337-43.  
21. Amtmann D, Cook KF, Johnson KL, Cella D. The PROMIS initiative: involvement of 
rehabilitation stakeholders in development and examples of applications in rehabilitation 
research. Arch Phys Med Rehabil 2011;92:S12-9.  
22. Eypasch E, Williams JI, Wood-Dauphinee S, et al. Gastrointestinal quality of life index: 
development, validation and application of a new instrument. Br J Surg 1995;82:216-22.  
23. Brehaut JC, O'Connor AM, Wood TJ, et al. Validation of a decision regret scale. Med 
Decis Making 2003;23:281-92.  
24. Le QA, Doctor JN, Zoellner LA, Feeny NC. Minimal clinically important differences for 
the EQ-5D and QWB-SA in post-traumatic stress Disorder (PTSD): results from a doubly 
randomized preference trial (DRPT). Health Qual Life Outcomes 2013;11:59,7525-11-59.  
25. Koumarelas K, Theodoropoulos GE, Spyropoulos BG, Bramis K, Manouras A, Zografos 
G. A prospective longitudinal evaluation and affecting factors of health related quality of life 
after appendectomy. Int J Surg 2014;12:848-57.  
26. Anonymous ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. 
International Conference on Harmonisation E9 Expert Working Group. Stat Med 
1999;18:1905-42.  
27. Turner L, Shamseer L, Altman DG, et al. Consolidated standards of reporting trials 
(CONSORT) and the completeness of reporting of randomised controlled trials (RCTs) 
published in medical journals. Cochrane Database Syst Rev 2012;11:MR000030.  
28. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ, CONSORT Group. 
Reporting of noninferiority and equivalence randomized trials: an extension of the 
CONSORT statement. JAMA 2006;295:1152-60.  
29. Calvert M, Blazeby J, Altman DG, et al. Reporting of patient-reported outcomes in 
randomized trials: the CONSORT PRO extension. JAMA 2013;309:814-22.  
30. Diggle PJ, Heagerty PJ, Liang KY, Zeger SL. Analysis of longitudinal data. London: 
Oxford University Press, 2002.  
31. Sitlani CM, Heagerty PJ, Blood EA, Tosteson TD. Longitudinal structural mixed models 
for the analysis of surgical trials with noncompliance. Stat Med 2012;31:1738-60.  
32. Detry MA, Lewis RJ. The intention-to-treat principle: how to assess the true effect of 
choosing a medical treatment. JAMA 2014;312:85-6.  
33. Angrist J, Imbens G. Two-stage least squares estimation of average causal effects in 
models with variable treatment intensity. J Amer Statist Assoc 1995;90:431-42.  
34. Little R, Yau L. Statistical techniques for analyzing data from prevention trials: 
Treatment of no-shows using Rubin’s causal model. Psychol Methods 1998;3:147-59.  


Flum/Talan 
Study Protocol Version 6.1 
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42 
 
35. Bloom H. Accounting for no-shows in experimental evaluation designs. Evaluation 
Review 1984;8:225-46.  
36. Tibshirani R. Regression shrinkage and selection via the lasso. J Royal Statistics 
Society B 1996;58:267-88.  
37. Hastie T, Tibshirani R, Friedman J. The elements of statistical learning. New York: 
Springer, 2009.  
38. Molenberghs G, Kenward MG. Missing data in clinical studies. J Trop Pediatr 
2007;53:294.  
39. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. 
Biometrika 1977;64:191-9.  
40. Bratton DJ, Williams HC, Kahan BC, Phillips PP, Nunn AJ. When inferiority meets non-
inferiority: implications for interim analyses. Clin Trials 2012;9:605-9.  
 

SAP_001.pdf: 
 
The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) Trial Statistical Analysis Plan 
Document Date: February 2020 
NCT02800785 
 
Note: Changes between first and final plans are noted immediately below, followed by the original SAP 
and final SAP 
Summary of Changes to the CODA Statistical Analysis Plan 
 
Research Aims 
• Sub Aim 1 modified to include patients with appendicolith in addition to without appendicolith to 
reflect the protocol. 
• Exploratory Aim A modified to reflect time windows of interest. 
• Sub Aim 2 modified to include patients with appendicolith in addition to without appendicolith to 
reflect the protocol. 
 
Study Design and Treatment Allocation 
• Block sizes changed from 4, 6, 8 and 10 to 4, 6, and 8. 
• Definition of “early antibiotic failure” removed. 
 
Outcome Measures: 
• Additional outcome measures of interest, defined in the protocol, were added. 
 
General Analytic Strategy: Unchanged. 
 
Primary Analysis, Aim 1: 
• Plan for Sub Aim 1 modified to include patients with appendicolith in addition to without 
appendicolith to reflect the protocol. 
• A plan for patients who were randomized using the incorrect appendicolith status was added. 
 
Aim 1 Secondary Analyses 
• GEE added as an option for analyzing longitudinal data. 
• Per protocol analysis added. 
 
Exploratory Aim A Analysis Plan: 
• Plan for defining appendectomies by reason and time added. 
 
Aim 2 Analysis Plan 
• Specific clinical endpoints removed since described previously. 


• Plan for Sub Aim 2 modified to include patients with appendicolith in addition to without 
appendicolith to reflect the protocol. 
 
Exploratory Aim B Analysis Plan: 
• GEE added as an option for analyzing longitudinal data. 
 
Additional Exploratory Subgroups:   
• Added in most recent version to reflect the protocol. 
Original plan starts here: 
Research Aims 
Aim 1: Compare PROs in patients randomized to antibiotics-first or appendectomy. 
Sub Aim 1. Compare patient reported outcomes (PROs) in patients without appendicolith randomized to the 
antibiotics or appendectomy strategy. 
 
Exploratory Aim A. Assess the rate of eventual appendectomy after starting the antibiotics treatment regimens 
in the first week, early (1-4 weeks) and late (2-24 months) periods and identify patient clinical characteristics 
(e.g., appendicolith) as well as clinician and practice site characteristics associated with eventual 
appendectomy in the antibiotic therapy group. 
. 
Aim 2: Compare clinical outcomes in patients randomized to antibiotics-first or appendectomy. 
 
Sub Aim 2. Compare clinical outcomes in patients without appendicolith randomized to the antibiotics or 
appendectomy strategy. 
 
Exploratory Aim B: Compare randomized patients to those in a concurrent observational cohort to identify 
selection characteristics and outcome differences between the two groups.  
 
Study Design and Treatment Allocation: This is a non-inferiority based, pragmatic, randomized controlled 
trial of antibiotics-first vs. appendectomy for the treatment of uncomplicated appendicitis with a concurrent 
observational cohort to characterize any selection bias associated with patients choosing to participate in the 
randomized trial, and to support the generalizability of study results. By necessity, this is an un-blinded study 
(patients will know if they were randomized to appendectomy or antibiotics), and analysts will know the 
treatment allocation of study participants. The DCC will generate and maintain randomization lists for each 
practice site. We will use block randomization within practice sites, with random blocks of 4, 6, 8 or 10 subjects. 
Using block randomization ensures that equal numbers of subjects are randomized to the intervention and 
control arm and that the two groups are balanced at periodic enrollment intervals. We will also stratify 
randomization on race to ensure balanced treatment assignments across racial subgroups.  Crossover, in 
the conventional manner, is defined as a patient who is randomized to appendectomy who refuses to undergo 
surgery or someone who is randomized to antibiotics but chooses appendectomy before the antibiotics are 
started. For the sake of convenience in describing statistical analysis and data monitoring plans, we define the 
term early antibiotics failures (or treatment changed) as patients in the antibiotics treatment arm who were 
treated with appendectomy with 4 weeks after randomization. 
Outcome Measures: The primary outcome is the EQ-5D at 4 weeks following randomization to treatment. 
Secondary patient reported outcome measures include the 10 PROMIS Global Health Short Form, the Decision 
Regret Scale, and Gastrointestinal Quality of Life Index (GIQLI). Clinical endpoints include: days until resolution 
of symptoms, rates of perforated appendicitis, extent of operative and surgical complications, complications 
associated with antibiotics, hospital days, number of days using antibiotics beyond the initial treatment 


schedule, clinic visits, and caregiver/patient “time in healthcare”. 
General Analytic Strategy: The primary evaluation of EQ-5D at 4 weeks will be conducted using an 
intention-to-treat (ITT) analysis, where patients’ data are analyzed according to the patients’ randomized 
treatment assignment. Using this analytic approach in a non-inferiority study design comparing antibiotics-first 
treatment to appendectomy, we aim to test whether the global EQ-5D scores are not different by more than a 
margin of 5% (M = 5%). The margin (5%) was selected because it is within the meaningful clinical important 
difference (MCID) threshold of the EQ-5D, which is 5-10%1-3.  
Primary Analysis, Aim 1: Patient-reported QoL, as measured by the EQ-5D at 4 weeks, will be assessed 
using a linear regression model that adjusts for an indicator of randomized treatment group assignment and for 
all factors used to stratify randomization (e.g., practice site, race). As recommended by the United States Food 
and Drug Administration guidelines on clinical trial design4, the estimated treatment effect and 97.5% one-sided 
confidence interval (CI) will be compared to the non-inferiority margin (M = -5%)5-7. We will conclude that 
antibiotics are non-inferior to appendectomy when the entire 97.5% one-sided confidence interval is greater 
than M, as in example scenario A (Figure 1). This is equivalent to a one-sided (alpha=0.025) test of the null 
hypothesis H0: Δ < -5%, where Δ represents the difference in mean EQ-5D at 4-weeks comparing antibiotics-
first to appendectomy-first. If the null hypothesis of H0: Δ < -5% is rejected at  
Figure 1. Example trial conclusions in a non-inferiority trial. 
the final evaluation, we will 
then conduct a test of 
superiority to determine the 
level of statistical evidence 
supporting an alternative 
hypothesis HA: Δ > 0% (i.e., 
scenario B of Figure 1). For 
Sub Aim 1, we will similarly 
evaluate non-inferiority on 
patient-reported QoL among 
the cohort without 
appendicolith.   
 
Aim 1 Secondary Analyses: 
Secondary analyses of the primary outcome measures will include examining the entire trajectory of EQ-5D 
QoL measurements for each patient using linear mixed effects models for longitudinal data.8 While crossovers 
and early antibiotics failures are anticipated, the ITT approach is an appropriate primary analysis. We will 
conduct a secondary as-treated analysis of the primary outcome measure that appropriately accounts for 
patient- or provider-level characteristics found to be differentially represented among patients who crossover 
and patients in the antibiotics arm who are treated with appendectomy. Careful as-treated and secondary data 
analyses are of elevated importance towards understanding the effectiveness of the treatments and in 
assessing for whom antibiotics-first is an appropriate treatment.9 A simple as-treated analysis is problematic 
because randomization is broken when select patients in the antibiotics-first arm ultimately receive 
appendectomy. Thus, patients who are successfully treated with antibiotics and do not undergo appendectomy 
may differ demographically or clinically in ways that introduce bias in a naive as-treated analysis. Detry (JAMA 
2014) recommends both an ITT and a careful as-treated analysis to address treatment changes in non-
inferiority trials where non-adherence, crossover, or treatment changes are present. If we find a difference 
between the ITT and as-treated results, the ITT results will be considered the primary analysis.10  
 
We will consider a two-stage approach for this as-treated analysis: 1) To identify subgroups that are likely to 
require appendectomy and therefore should not be considered as good candidates for treatment with 
antibiotics-first, and 2) To estimate the complier average causal effect (CACE), which seeks to compare the 
outcomes of patients treated successfully in the antibiotics-first arm (i.e., did not ultimately have surgery) with 
patients randomized to the appendectomy arm who similarly would not have crossed over had they been 


randomized to the antibiotics-first arm. The CACE framework considers the ITT mean in each randomized 
arm as being comprised of two subgroup means: patients who would be successfully treated with antibiotics-
first without appendectomy, and patients who would eventually require appendectomy after being treated with 
antibiotics-first. We are able to directly observe which patients in the antibiotics-first arm ultimately cross over, 
but require the CACE framework to identify similar patients in the appendectomy arm. We will use a maximum 
likelihood mixture modeling approach to identify the optimal comparison group from the control arm for 
observed compliers in the intervention arm.11 This application of mixture modeling permits an examination of 
two aspects of intervention process, the prediction of early antibiotics failures in the appendectomy-first group 
and the examination the treatment effect on quality of life among patients who are suitable candidates for 
treatment with antibiotics first.12  
 
Analysis of Secondary Patient-Reported Outcomes: We will also compare secondary patient reported 
outcomes (i.e., 10 PROMIS Global Health Short Form, GIQLI, and the Decision Regret Scale) using an ITT 
framework and linear regression models. Similar to the primary outcome measure, secondary patient-reported 
outcomes will be assessed using model-based point estimates and associated confidence intervals. The 
magnitude of effect will be judged a posteriori using margins that are of comparable magnitude as the EQ-5D in 
terms of the Cohen’s d statistic. In an exploratory analysis, the complete longitudinal trajectory of all PRO 
metrics will be assessed with linear mixed effects models.  
Exploratory Aim A Analysis Plan: Using only data from patients enrolled in the antibiotics-first arm, we will 
also examine the association of these characteristics with eventual appendectomy. We will employ univariate 
logistic regression models to identify and characterize associations with unplanned appendectomy. If we find 
that a number of baseline characteristics are relevant and the rate of unplanned appendectomy is high enough 
(e.g., >10-15%), we will use multivariable analyses to compare these characteristics among those 
undergoing early appendectomy (defined within the first 4 weeks) and eventual appendectomy (4 weeks to 2 
years). Due to the potentially large number of input variables, interactions, and longitudinal assessments we 
will also use modern model development methods such as the LASSO with boosting.13,14  Boosting provides a 
more sophisticated approach towards building multivariable predictive models and allows nonlinear 
relationships between the input variables and risk of requiring appendectomy after first being treated with 
antibiotics. Boosting is a multiple prediction and aggregation method for classification, where a “base learner” 
fitting method is fitted multiple times on reweighted data and a final estimator is constructed through a linear 
combination of the multiple estimates. Results of these analyses will be considered hypothesis generating 
and may support secondary studies aimed at predictive modeling. 
 
Aim 2 Analysis Plan: Clinical endpoints (e.g., days until resolution of symptoms, rates of perforated 
appendicitis, extent of operation and surgical complications, complications associated with antibiotics, hospital 
days, number of days using antibiotics beyond the initial treatment, clinic visits, and caregiver/patient “time in 
healthcare”) will also be compared between ITT groups using regression models appropriate to each endpoint 
(e.g., linear, logistic, Poisson, or Cox proportional hazards regression models), along with a similar non-
inferiority framework with margins based on MCIDs. For Sub Aim 2, we will similarly evaluate clinical endpoints 
among the cohort without appendicolith.   
 
Exploratory Aim B Analysis Plan: One assumption is that patients included in the randomized trial are 
sufficiently similar to those from the general population of patients with appendicitis. Using simple univariate 
descriptive and comparative statistics (e.g., t-tests, Chi-squared tests), we will compare randomized patients to 
those in the parallel observational cohort to identify selection bias. We will also compare the primary outcome 
measures between randomized and non-randomized patients by examining the entire trajectory of EQ-5D QoL 
measurements using linear mixed effects models for longitudinal data, providing an assessment of differences 
in the rate of change of quality of life. We will adjust for patient- or provider-level characteristics found to be 
differentially represented in RCT. Using methods similar to those described in the plan for Aim 1 Secondary 
Analyses, we will adjust for treatment received to fully assess whether patients who participate in the RCT have 
a different outcome trajectory than patients in the observational cohort. 


Missing Data: We will conduct a missing data analysis to describe and characterize enrolled participants who 
do not provide data due to attrition. As described by Molenberghs and Kenward (2007), we will use inverse 
probability weighting in secondary analysis within each longitudinal regression model to inflate the weights of 
cases that are under-represented in the analysis due to selective attrition and/or non-participation. We will also 
conduct sensitivity analyses using 10-fold multiple imputation to assess the robustness of the results when 
missing data are imputed. We will assess the sensitivity of inferences made from missing data first by using the 
two previously described methods for dealing with missing data and second, by imputing missing data under 
both pessimistic and optimistic scenarios to provide bounds on the statistical uncertainty. The characteristics of 
non-responders will be summarized in our final report and we will present the sensitivity of the estimated 
treatment effect due to alternative missing data methods. 
 
 


 
Statistical Analysis Plan References 
 
1. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001 
Jul;33(5):337-43. PMID:11491192   
2. Le QA, Doctor JN, Zoellner LA, Feeny NC. Minimal clinically important differences for the EQ-5D and QWB-
SA in Post- traumatic Stress Disorder (PTSD): results from a Doubly Randomized Preference Trial (DRPT). 
Health Qual Life Outcomes. 2013 Apr 12;11:59. PMID:23587015   
3. Koumarelas K, Theodoropoulos GE, Spyropoulos BG, et al. A prospective longitudinal evaluation and 
affecting factors of health related quality of life after appendectomy. Int J Surg. 2014;12(8):848-57. 
PMID:25019228   
4. International Conference on Harmonisation E9 Expert Working Group. (1999). ICH harmonised tripartite 
guideline: statistical principles for clinical trials. Stat Med 18(15):1905-42. PMID:10532877   
5. Turner L, Shamseer L, Altman DG, et al. Consolidated standards of reporting trials (CONSORT) and the 
completeness of reporting of randomised controlled trials (RCTs) published in medical journals. Cochrane 
Database Syst Rev. 2012 Nov 14;11:MR000030. PMID:23152285   
6. Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG; CONSORT Group. Reporting of noninferiority 
and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012 Dec 
26;308(24):2594-604. PMID:23268518   
7. Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD; CONSORT PRO Group. Reporting of 
patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013 Feb 
27;309(8):814-22. PMID:23443445  
8. Diggle PJ, Heagerty PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data. Second Edition ed: Oxford 
University Press; 2002.   
9. Sitlani CM, Heagerty PJ, Blood EA, Tosteson TD. Longitudinal structural mixed models for the analysis of 
surgical trials with noncompliance. Stat Med. 2012 Jul 20;31(16):1738-60. PMID:22344923. 
PMCID:PMC3876882 
10. Detry MA, Lewis RJ. The intention-to-treat principle: how to assess the true effect of choosing a medical 
treatment. JAMA. 2014 Jul 2;312(1):85-6. PMID:25058221 
11. Angrist J, Imbens G. Two-stage least squares estimation of average causal effects in models with variable 
treatment intensity. Journal of the American Statistical Association. 1995;90:431–442. 
12. Little R, Yau L. Statistical techniques for analyzing data from prevention trials: Treatment of no-shows using 
Rubin’s causal model. Psychological Methods. 1998;3:147–159; Bloom, H. (1984). Accounting for No-Shows in 
Experimental Evaluation Designs. Evaluation Review 8(2), 225-246. 
13. Tibshirani, R. (1996). Regression shrinkage and selection via the lasso, J. Royal Statistics Society B. 58: 
267-288. 
14. Hastie T, Tibshirani R, Friedman J. The Elements of Statistical Learning. Second Edition: Springer; 2009.   
15. Molenberghs G, Kenward MG. Missing Data in Clinical Studies. J Trop Pediatr 2007;53(4):294. Retrieved 
at: http://tropej.oxfordjournals.org/content/53/4/294.full   
16. Pocock SJ (1977). "Group sequential methods in the design and analysis of clinical 
trials". Biometrika 64 (2): 191–9. doi:10.1093/biomet/64.2.191. 
17. Bratton DJ, Williams HC, Kahan BC, Phillips PP, Nunn AJ. When inferiority meets non-inferiority: 
implications for interim analyses. Clin Trials. 2012 Oct;9(5):605-9. doi: 10.1177/1740774512453220. Epub 2012 
Jul 13. 


 
Final SAP starts here: 
Research Aims 
 
Aim 1: Compare PROs in patients randomized to antibiotics-first or appendectomy. 
 
Sub Aim 1. Compare patient reported outcomes (PROs) in patients with and without appendicolith 
randomized to the antibiotics or appendectomy strategy. 
 
Exploratory Aim A. Assess the rate of eventual appendectomy after starting the antibiotics treatment 
regimens in the first 48 hours, early (30 days) and late (1 year) periods and identify patient clinical 
characteristics (e.g., appendicolith) as well as clinician and practice site characteristics associated with 
eventual appendectomy in the antibiotic therapy group. 
 
Aim 2: Compare clinical outcomes in patients randomized to antibiotics-first or appendectomy. 
 
Sub Aim 2. Compare clinical outcomes in patients with and without appendicolith randomized to the 
antibiotics or appendectomy strategy. 
 
Exploratory Aim B: Compare randomized patients to those in a concurrent observational cohort to identify 
selection characteristics and outcome differences between the two groups. 
 
Study Design and Treatment Allocation: This is a non-inferiority based, pragmatic, randomized controlled 
trial of antibiotics-first vs. appendectomy for the treatment of uncomplicated appendicitis with a concurrent 
observational cohort to characterize any selection bias associated with patients choosing to participate in the 
randomized trial, and to support the generalizability of study results. By necessity, this is an un-blinded study 
(patients will know if they were randomized to appendectomy or antibiotics), and analysts will know the 
treatment allocation of study participants. The DCC will generate and maintain randomization lists for each 
practice site. We will use block randomization within practice sites, with random blocks of 4, 6, or 8 subjects. 
Using block randomization ensures that equal numbers of subjects are randomized to theintervention and 
control arm and  thatthe two groups  are balanced at periodic    enrollment intervals. W e will 
also stratify 
randomization on presence  appendicolith  determined  by  imaging  to  ensure  balanced 
treatmentassignments 
across this important subgroup. Crossover, in  the conventional  manner, is defined 
as a patient who is randomized to appendectomy who refuses to undergo surgery or someone who is 
randomized to antibiotics but chooses appendectomy before or after the antibiotics are started. Please see 
below for our specific definition of protocol compliance that will be used for a per-protocol analysis. 
Outcome Measures: The primary outcome is the EQ-5Dat 
4 weeks following randomization to treatment. 
Secondary patient reported outcome measures include the 10 PROMIS Global Health Short Form, the 
Decision Regret Scale, Gastrointestinal Quality of Life Index (GIQLI), healthcare utilization, days missed of 
work, days a caregiver missed of work, and work productivity. Clinical endpoints include: resolution of 
symptoms, rates of appendectomy, rates of appendicitis-related events (e.g., perforated  appendicitis, 
additional course of antibiotics, more extensive surgical procedure, and drainage procedures), extent of 
operative and surgical complications, neoplasm and other pathology findings, adverse and serious adverse 
events, hospital days, clinic visits, and caregiver/patient “time in healthcare”. 
 
General Analytic  Strategy: The primary evaluation  of EQ-5Dat 4 weeks will be conductedusing an 
intention-to-treat  (ITT)analysis, 
where patient  data  areanalyzed according to 
the patient’s randomized 
treatment assignment. Using this analytic approach in a non-inferiority study design comparing antibiotics- 
first treatment to appendectomy, we aim to test whether the global EQ-5D scores are not different by more 
than a margin of 5% (M = 5%). The margin (5%) was selected because it is within the meaningful clinical 


important difference (MCID) threshold of the EQ-5D, which is 5-10%1-3. 


Primary Analysis, Aim 1: Patient-reported QoL, as measured by the EQ-5D at  4 weeks, will be assessed 
using a linear regression model that adjusts for an  indicator of randomized treatment group  assignment and 
for all factors used to stratify randomization (i.e., practice site and appendicolith). As recommended by the 
United States Food and Drug Administration guidelines on clinical trial design4, the estimated treatment effect 
and 97.5% one-sided confidence interval (CI) will be compared to the non-inferiority margin (M = -5%)5-7. We 
will conclude that antibiotics are non-inferior to appendectomy when the entire 97.5% one-sided confidence 
interval is greater  than M,  as in  example scenario A (Figure 1). This  is  equivalent  to a one-sided 
(alpha=0.025) test of the null hypothesis H0: Δ < -5%, where Δ represents the difference in mean EQ-5D at 4- 
weeks comparing antibiotics-first to appendectomy-first. If the null hypothesis of H0: Δ < -5% is rejected at 
Figure 1. Example trial conclusions in a non-inferiority trial. 
the final evaluation, we will 
then conduct a test of 
superiority to determine the 
level of statistical evidence 
supporting an alternative 
hypothesis HA: Δ > 0% (i.e., 
scenario B of Figure 1). For 
Sub Aim 1, we will similarly 
evaluate non-inferiority on 
patient-reported QoL 
among the cohort with and 
without appendicolith. 
Patients whose 
randomization was 
performed for the incorrect appendicolith group (e.g., research coordinator selected the wrong button during 
randomization) will be assigned to the group representing their true status. 
 
Aim 1 Secondary Analyses: Secondary analyses of the primary outcome measures will include examining 
the entire trajectory of EQ-5D QoL measurements for each patient using statistical methods for longitudinal 
data such as linear mixed effects models or generalized estimating equations (GEE).8 
 
While crossovers are anticipated, the ITT approach is an appropriate primary analysis. We will conduct a 
secondary as-treated analysis of the primary outcome measure that appropriately accounts for patient- or 
provider-level characteristics found to be  differentially  represented among patients  who crossover and 
patients in the antibiotics arm who are treated with appendectomy. Careful as-treated and secondary data 
analyses are of elevated importance towards understanding the effectiveness of the treatments and in 
assessing for whom antibiotics-first is an appropriate treatment.9 A simple as-treated analysis is problematic 
because randomization is broken when select patients in the antibiotics-first arm ultimately receive 
appendectomy. Thus, patients who are successfully treated with antibiotics and do not  undergo 
appendectomy may differ demographically or clinically in ways that introduce bias in a naive as-treated 
analysis. Detry (JAMA 2014) recommends both an ITT and a careful per-protocol analysis to address 
treatment changes in non-inferiority trials  where non-adherence,  crossover, or treatment changes  are 
present. If we find a difference between the ITT and as-treated results, the ITT results will be considered the 
primary analysis.10 
 
Per-Protocol Analysis: It is important to consider subjects who do not follow the protocol since these 
individuals bias treatment group comparisons toward no difference, but this is  the alternative  hypothesis 
rather than the null hypothesis for non-inferiority trials. Therefore, it is recommended that an ITT analysis is 
augmented with a per-protocol analysis that considers only those subjects from both treatment groups who 
adhered to the protocol. Although such a subset analysis may have bias due to patient factors associated 


with non-adherence to the protocol it is a valuable companion analysis that does not suffer from non- 
adherence bias in the way that ITT analysis may. Our protocol states the conditions that are considered to 
adhere to the protocol, therefore we use the following criteria: 
• All patients: exclude not randomized in accordance to the protocol (i.e., meets all 
inclusion/exclusion criteria, randomization assignment followed) 
• 
Surgical group: exclude subjects whose randomization assignment was ignored. 
• Antibiotics group: exclude subjects whose randomization assignments were ignored, were not 
given protocol-described antibiotics, or who underwent an appendectomy (for non-protocol 
indications, as described by sites). 
For the antibiotics group we have a direct measurement of whether eventual surgery is compliant with the 
protocol as reported by the sites. In the per-protocol analysis we will exclude subjects according to the 
criterion above, and then analyze EQ5D using mean differences and the associated confidence interval to 
judge non-inferiority similar to our ITT analysis plan. 
 
As-Treated Analysis: We will consider a two-stage approach for this as-treated analysis: 1) To identify 
subgroups that are likely to require appendectomy  and therefore  should not  be considered as  good 
candidates for treatment with antibiotics-first, and 2) To estimate the complier average causal effect (CACE), 
which seeks to compare the outcomes of patients treated successfully in the antibiotics-first arm (i.e., did not 
ultimately have surgery) with patients randomized to the appendectomy arm who similarly would not have 
crossed over had they been randomized to the antibiotics-first arm. The CACE framework considers the 
ITT mean in each randomized arm as being comprised of two subgroup means: patients who would be 
successfully treated with antibiotics-first without appendectomy, and patients who would eventually require 
appendectomy after being treated with antibiotics-first. We are able to directly observe which patients in the 
antibiotics-first arm ultimately cross over, but require the CACE framework to identify similar patients in the 
appendectomy arm. We will use a maximum likelihood mixture modeling approach to identify the optimal 
comparison group from the control arm for observed compliers in the intervention arm.11 This application of 
mixture modeling permits an examination of two aspects of intervention process, the prediction of early 
antibiotics failures in the appendectomy-first group and the examination the treatment effect on quality of life 
among patients who are suitable candidates for treatment with antibiotics first.12 
 
Analysis of Secondary Patient-Reported Outcomes: We will also compare secondary patient reported 
outcomes (i.e., 10 PROMIS Global Health Short Form, GIQLI, and the Decision Regret Scale) using an ITT 
framework and linear regression models. Similar to the primary outcome measure, secondary patient- 
reported outcomes will be assessed using model-based point estimates and associated confidence intervals. 
The magnitude of effect will be judged a posteriori using margins that are of comparable magnitude as the EQ-
5D in terms of the Cohen’s  d statistic. In  an exploratory  analysis, the complete longitudinal  trajectory  of all 
PRO metrics will be assessed with linear mixed effects models. 
 
Exploratory Aim A Analysis Plan: Using only data  from  patients  enrolled  in  the  antibiotics-first  arm, we 
will also examine the association of  these  characteristics  with  eventual  appendectomy. The primary 
analysis will consider appendectomies performed for any reason. A secondary analysis will define 
appendectomies as those performed for: (1) acute clinical reason 0-30 days post randomization, (2) non- 
acute clinical reason and (3) recurrence after a period of symptom resolution (30+ days post randomization). 
 
We will employ univariate logistic regression models to identify and characterize associations with unplanned 
appendectomy. If we find that a number of baseline characteristics are relevant and the rate of unplanned 
appendectomy is high enough (e.g., >10-15%), we will use multivariable analyses to compare these 
characteristics among those undergoing  early  appendectomy  (defined  within  the  first  30  days)  and 
eventual appendectomy (4 weeks to 2 years). Due to the potentially large number of input  variables, 
interactions, and longitudinal assessments we will also use modern model development methods such as the 
LASSO with boosting.13,14 Boosting provides a more sophisticated approach towards building multivariable 


predictive models and allows nonlinear relationships between the input variables and risk of requiring 
appendectomy after first being treated with antibiotics. Boosting is  a multiple prediction and  aggregation 
method for classification, where a “base learner” fitting method is fitted multiple times on reweighted  data  and 
a final estimator is constructed through a linear combination of the multiple estimates. Results of these 
analyses will be considered hypothesis generating and may support secondary studies aimed at 
predictive modeling. 
 
Aim 2 Analysis Plan: Clinical endpoints (see Outcome Measures above) will also be compared between ITT 
groups using regression models appropriate to each endpoint  (e.g., linear,  logistic, Poisson, or Cox 
proportional hazards regression models), along with a similar  non-inferiority  framework with margins  based 
on MCIDs when available. For Sub Aim 2, we will similarly evaluate clinical endpoints among the cohort with 
and without appendicolith. The goal is to estimate treatment effects within each subgroup based on 
appendicolith. 
 
Exploratory Aim B Analysis Plan: One assumption is that patients included in the randomized trial are 
sufficiently similar to those from the general population of patients with appendicitis. Using simple univariate 
descriptive and comparative statistics (e.g., t-tests, Chi-squared tests), we will compare randomized patients 
to those in the parallel observational cohort to identify selection bias. We will also compare the primary 
outcome measures between randomized and non-randomized patients by examining the entire trajectory of 
EQ-5D QoL measurements using linear mixed effects models or GEE for longitudinal data, providing an 
assessment of differences in the rate of change of quality of life. We will adjust for patient- or provider-level 
characteristics found to be differentially represented in RCT. Using methods similar to those described in the 
plan for Aim 1 Secondary Analyses, we will  adjust for  treatment received  to fully  assess whether patients 
who participate in the RCT have a different outcome trajectory than patients in the observational cohort. 
Missing Data: We will conduct a missing data analysis to describe andcharacterize enrolled participants 
who do not provide data due to attrition. Specifically, we use 10-fold multiple imputation to assess the 
robustness of the results when missing data are imputed. In addition, as described by Molenberghs and 
Kenward (2007), we will also use inverse probability weighting in secondary analysis within each longitudinal 
regression model to inflate the weights of cases that are under-represented in the analysis due to selective 
attrition and/or non-participation. We will assess the sensitivity of inferences made from missing data first by 
using the two previously described methods for dealing with missing data and second, by imputing missing 
data under both pessimistic and optimistic scenarios to provide bounds on the statistical uncertainty. The 
characteristics of non-responders will be summarized in our final report and we will present the sensitivity of 
the estimated treatment effect due to alternative missing data methods. 
 
Additional Exploratory Subgroups: We will also evaluate outcomes in selection subgroups including 
advanced age, sex, comorbid conditions and insurance status. For these analyses we will focus on 
evaluation of statistical interactions with treatment to assess treatment effect heterogeneity. 


 
Statistical Analysis Plan References 
 
1. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001 
Jul;33(5):337-43. PMID:11491192 
2. Le QA, Doctor JN, Zoellner LA, Feeny NC. Minimal clinically important differences for the EQ-5D and 
QWB-SA in Post- traumatic Stress Disorder (PTSD): results from a Doubly Randomized Preference 
Trial (DRPT). Health Qual Life Outcomes. 2013 Apr 12;11:59. PMID:23587015 
3. Koumarelas K, Theodoropoulos GE, Spyropoulos BG, et al. A prospective longitudinal evaluation and 
affecting factors of health related quality of life after appendectomy. Int J Surg. 2014;12(8):848-57. 
PMID:25019228 
4. International Conference on Harmonisation E9 Expert Working Group. (1999). ICH harmonised 
tripartite guideline: statistical principles for clinical trials. Stat Med 18(15):1905-42. PMID:10532877 
5. Turner L, Shamseer L, Altman DG, et al. Consolidated standards of reporting trials (CONSORT) and the 
completeness of reporting of randomised controlled trials (RCTs) published in medical journals. 
Cochrane Database Syst Rev. 2012 Nov 14;11:MR000030. PMID:23152285 
6. Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG; CONSORT Group. Reporting of noninferiority 
and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA. 2012 Dec 
26;308(24):2594-604. PMID:23268518 
7. Calvert M, Blazeby J, Altman DG, Revicki DA,  Moher  D, Brundage MD;  CONSORT PRO Group. Reporting 
of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA. 2013 Feb 
27;309(8):814-22. PMID:23443445 
8. Diggle PJ, Heagerty PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data. Second Edition ed: Oxford 
University Press; 2002. 
9. Sitlani CM, Heagerty PJ, Blood EA, Tosteson TD. Longitudinal structural mixed models for the analysis 
of surgical trials with noncompliance. Stat Med. 2012 Jul 20;31(16):1738-60. PMID:22344923. 
PMCID:PMC3876882 
10. Detry MA, Lewis RJ. The intention-to-treat principle: how to assess the true effect of choosing a 
medical treatment. JAMA. 2014 Jul 2;312(1):85-6. PMID:25058221 
11. Angrist J, Imbens G. Two-stage least squares estimation of average causal effects in models 
with variable treatment intensity. Journal of the American Statistical Association. 1995;90:431–
442. 
12. Little R, Yau L. Statistical techniques for analyzing data from prevention trials: Treatment of no-shows 
using Rubin’s causal model. Psychological Methods. 1998;3:147–159; Bloom, H. (1984). Accounting for 
No- Shows in Experimental Evaluation Designs. Evaluation Review 8(2), 225-246. 
13. Tibshirani, R. (1996). Regression shrinkage and selection via the lasso, J. Royal Statistics Society B. 
58: 267-288. 
14. Hastie T, Tibshirani R, Friedman J. The Elements of Statistical Learning. Second Edition: Springer; 2009. 
15. Molenberghs G, Kenward MG. Missing Data in Clinical Studies.  J Trop Pediatr  2007;53(4):294.  
Retrieved at: http://tropej.oxfordjournals.org/content/53/4/294.full 
16. Pocock SJ (1977). "Group sequential methods in the design and analysis of 


clinical trials". Biometrika 64 (2): 191–9. doi:10.1093/biomet/64.2.191. 
17. Bratton DJ, Williams HC, Kahan BC, Phillips PP, Nunn AJ. When inferiority meets non-inferiority: 
implications for interim analyses. Clin Trials. 2012 Oct;9(5):605-9. doi: 10.1177/1740774512453220. 
Epub 


Comparing Outcomes of Drugs and Appendectomy (CODA) 
STATISTICAL ANALYSIS PLAN 
 
 
 
Page 14 of 
14 
2012 Jul 13.