Secondary Outcome Measures : Days until resolution of appendicitis symptoms [ Time Frame: at 7 days, 14 days and between days ] Days until resolution of appendicitis symptoms measured as absence of fever and abdominal pain and tenderness. Rates of perforated appendicitis will be compared between ITT groups using regression models. Surgical complications and antibiotics complications will be compared between ITT groups using regression models.
Rates of appendiceal cancer will be compared between ITT groups using regression models. Hospital days will be compared between ITT groups using regression models. Days using antibiotics beyond the initial treatment schedule will be compared between ITT groups using regression models. The number of clinic visits will be compared between ITT groups using regression models. We will also compare secondary patient-reported outcomes using an ITT framework and linear regression models.
Eventual appendectomy in patients randomized to antibiotics. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. AUA is defined by the usual signs, symptoms, and imaging finding of appendicitis without: Diffuse peritonitis on clinical exam i. Ability to provide written or electronic informed consent in English or Spanish. Exclusion Criteria: 1. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. More Information. N Engl J Med. Epub Oct 5. Comparison of Outcomes of antibiotic Drugs and Appendectomy CODA trial: a protocol for the pragmatic randomised study of appendicitis treatment. BMJ Open. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Not Applicable. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Study Start Date :. Actual Primary Completion Date :. Actual Study Completion Date :. Active Comparator: Antibiotics Therapy Arm 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.
The use of radiologic imaging to accurately determine perforation is limited; in prior randomised trials, patients with perforation were likely to have been inadvertently included due to a lack of imaging.
The Comparing Outcomes of Antibiotic Drugs and Appendectomy CODA trial was designed to address this question and inform decision-making, focusing on commonly used surgical strategies and a range of antibiotic strategies, including total outpatient therapy, across a broad range of practice environments and a heterogeneous group of patients.
These questions provide strong motivation for a pragmatic trial of antibiotics for acute appendicitis. A central feature of the CODA trial is its engagement of stakeholders in study conception, design, and implementation of the trial. The SCC engages representatives from the patient population of interest those at risk for or who have had appendicitis , clinicians who are involved in appendicitis treatment including emergency physicians, nurses and surgeons , leaders of professional societies American College of Surgeons and American College of Emergency Physicians , representatives of Accountable Care Organizations, policy-makers, insurers and payers, researchers and leaders from large self-insured employers.
Specific areas of protocol development informed by SCC included selecting primary and secondary outcomes. In addition to the routine clinical metrics that are assessed in any study of appendicitis treatment, other outcome measures important to patients anxiety, quality of life QoL , time away from work, out-of-pocket expenses and employers time away from work and productivity at work were included.
Because appendectomy was considered the standard and nearly universal therapy in the USA, advisors recommended a study that considered the non-inferiority of the antibiotics-first strategy.
Advisors also favoured a non-inferiority framework because the larger size required for this design would also allow for multiple planned subgroup analyses for patient groups of interest and the possibility that superiority of the PRO measure might be demonstrated. Lastly, advisors suggested a parallel observational cohort to assess for potential selection bias for patients who declined randomisation.
Patient advisors with an experience of incidentally identified neoplasm at the time of appendectomy helped modify the inclusion criteria excluding all patients with suggestion of mass of the appendix on imaging and consent form adding language to make sure that patients were informed about this risk, estimated to be 0. The aims of the study are to compare PROs and clinical outcomes in patients randomised to antibiotics or appendectomy.
We hypothesise that antibiotics are non-inferior to appendectomy for PROs and that there are subgroups with better outcomes clinical and patient reported with either treatment. A second set of aims is to perform subpopulation analyses for patients with appendicolith and imaging correlates that may indicate higher risk of requiring appendectomy following initiation of antibiotic therapy, advanced age, sex, comorbid conditions and insurance status.
Inability to participate in follow-up ie, incarcerated, travel without access to phone, email. Phlegmon for which surgery would not be recommended or diffuse peritonitis for which antibiotics alone would not be recommended. Participants who decline randomisation are asked to participate in the observational cohort with similar baseline and follow-up measures as participants in the randomised controlled trial.
All patients are asked for permission to be followed through passive electronic medical record EMR review. If a participant requests to speak with a medical provider or has concerning medical symptoms reported to the research team, the clinical team via the surgical site lead is contacted to call the participant for further follow-up. These reports identify missing values for required fields, incorrect data type, range checks, outliers, hidden fields that contain values and multiple-choice fields with invalid values.
Values that need to be corrected are brought to the attention of the research staff at that site. The first dose of antibiotics is given in the ED at the time of diagnosis of appendicitis, and a total outpatient regimen of antibiotics is an option for patients meeting ED discharge criteria.
Antibiotics are procured from the pharmacy by the patient as per usual clinical care. The decision to perform an appendectomy in participants randomised to antibiotics is made by the treating surgeon after consultation with the study clinical research lead to confirm that the above criteria have been satisfied. Standard discharge criteria are applied to those treated in the ED and those who are admitted, and the criteria include tolerance of liquids, adequate pain control and improving clinical condition.
Follow-up with the clinical team is per usual care at each institution. Participants in the antibiotics arm who return to any of the study sites during the follow-up period with recurrent appendicitis are not rerandomised but are offered the choice of either appendectomy or another antibiotic course, if treating surgeon agrees that their recurrence can be treated with either option.
All patients randomised to appendectomy receive preoperative antibiotics per hospital standards for surgical infection prevention protocols. Appendectomy is performed by an open or laparoscopic approach, depending on patient and surgeon preference.
This is an unblinded study as patients will know if they were randomised to appendectomy or antibiotics. Using block randomisation optimises the chances of equal numbers of subjects being randomised to each treatment arm, and that treatment is balanced at periodic enrolment intervals. Randomisation is further stratified by the presence of appendicolith.
All other subgroups of interest will be sufficiently large such that the risk of a meaningful imbalance in treatment groups by chance is unlikely. A web-based portal provides the randomised treatment assignment. Complications in both treatment groups are tracked and adjudicated by an independent safety monitor to determine their relation to the disease and treatment. The sample size was calculated based on the difference in EQ-5D between the two treatment interventions table 2.
As recommended by the US Food and Drug Administration guidelines on clinical trial design, the estimated treatment effect and There are four possible study conclusions. A The observed treatment effect black circle of antibiotics is almost zero and the B The observed treatment effect of antibiotics is more than 2. C The observed treatment effect of antibiotics is 2. We will separately assess treatment effect heterogeneity by adding to the primary outcome model an interaction term between the categorical subgroup variable of interest and the indicator of treatment.
We will use a global likelihood ratio test to examine if the treatment effect differs between key subgroups of interest. An ITT approach will be applied in the primary 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 good candidates for treatment with antibiotics as primary treatment strategy and 2 to estimate the complier average causal effect, which seeks to compare the outcomes of patients treated successfully in the antibiotic treatment arm ie, did not ultimately have surgery with patients randomised to the appendectomy arm who are similar in their expected compliance to assigned treatment.
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.
Death, life-threatening events and rehospitalisation other than for treatment of appendicitis are classified as serious adverse events SAEs.
AEs, SAEs and appendectomy after starting antibiotic treatment are identified through three approaches; EMR review, patient surveys and ad hoc reporting by any research or care team member. All SAEs are adjudicated by an independent safety monitor.
An independent DSMB reviews the accruing data to 1 ensure that study conduct, enrolment 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 analysis of accruing data is completed by the DCC, and interim analysis is presented to the DSMB with the primary goal of monitoring safety outcomes by randomisation group. The DSMB will conduct interim analyses at 12, 24 and 36 months. The CODA trial does not include a stopping rule if non-inferiority is met before complete accrual or if it is determined that non-inferiority cannot be demonstrated in interim analyses.
We are not employing a stopping rule because there are important secondary outcomes eg, rate of eventual appendectomy, complications, subgroup analysis and understudied subgroups that require full enrolment.
Prior trials randomising patients with appendicitis to antibiotics compared with appendectomy focused on disease cure, with the primary outcome being the rate of appendectomy among antibiotic-treated participants.
One of the greatest novelties of the CODA trial is its patient centredness, demonstrated both by the engagement of patients and other stakeholders as partners in selecting the topic, designing the proposal, developing the protocol and overseeing operations and in the selection of a QoL endpoint for the primary analysis.
CODA was designed to directly inform patient and clinician decision making in the community, and several pragmatic features were added to make sure it accounted for the diverse aspects of the population, practice settings and practices in the USA.
As a pragmatic trial, CODA has limited exclusion criteria and incorporates the many ways clinical care is delivered across sites of practice. The protocol allows patients in either study arm to leave the healthcare setting as soon as standard discharge criteria are met, including the possibility of completely outpatient care. CODA takes place in diverse study sites academic, private, public, community and county hospitals with patients from a wide range of demographic and socioeconomic characteristics, including both Spanish and English speakers.
This enhances the generalisability of the findings, but may compromise study fidelity if patients in any one group have differential treatment preferences or prove more difficult to contact for follow-up. A downside to this approach is that, by including nearly all patients with appendicitis including those with appendicolith and radiographic findings of perforation who may be at higher risk for requiring an appendectomy and those undergoing total outpatient antibiotics which clinicians have less experience with , there is a risk of subgroups with very different outcomes from the broader population and a skewing of the average study results.
The results from the European trials of antibiotics have not significantly changed care delivery in the USA and have been met with resistance, in part due to the evidence gaps cited earlier and concern about the fate of patients with recurrent disease. One particular protocol component of the European trials that may make them less applicable to the US experience is that prior studies all required an inhospital convalescence for a fixed period of time for both treatment arms that is double the length of stay that the average US patient experiences.
CODA builds on the successful experience of emergency medicine clinicians to manage patients with potentially serious infections as outpatients using risk stratification and long-acting parenteral antibiotics eg, diverticulitis , and its effectiveness will be tested in different practice settings and populations.
This novel treatment alternative offers avoidance of hospital admission and may substantially reduce costs compared with surgical treatment,. Stakeholder input is a key component of the emerging field of patient-centred outcomes research. However, including several types of stakeholders patients, physicians, payers and purchasers does not always result in consensus. The selection of an appropriate analytic outcome for the trial was an example.
While prior studies focused on clinical outcome eg, rates of appendectomy and surgical complications , patient advisors recognised that these outcome measures are specific to only one treatment arm and to people treated with antibiotics who proceed to appendectomy and that standardised measurements of QoL would be applicable to both and had yet to be rigorously assessed. The EQ-5D has been used in prior studies of appendectomy, but never in comparisons of these two treatments.
There is a possibility that the primary analytic outcome analysis non-inferiority of the EQ-5D could be positive, but other outcome domains might not be aligned. For this reason, multiple secondary analyses and exploratory endpoints have been selected a priori. Evidence in the field of decision-making suggests that patients want information on multiple domains, but we recognise that multiple outcome domains may also add confusion to interpretation of results and implementation in future practice.
However, recent research has challenged the dominance of the surgical approach in looking at antibiotics alone. The available literature on non-operative treatment of appendicitis NOTA has important limitations: exclusion of patients with appendicoliths, small sample size and predominance of open appendectomy over laparoscopic appendectomy.
While data on NOTA is intriguing, it is clear that additional studies are needed. Click here for Direct Download of Podcast. NEJM PMID: Clinical Question: In adult patients, are antibiotics noninferior to surgery for the treatment of acute appendicitis? In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith.
Clinical Take Home Point: Although an antibiotic 1 st strategy was non-inferior in this trial compared to appendectomy, nearly 3 in 10 patients had undergone appendectomy by 90 days, there were 3x more ED visits, and 2x more complications This could be balanced with less days of missed work.
Patients with an appendicolith are at a much higher risk of complications and need for surgery and in these patients an antibiotic 1 st strategy should not be recommended. Hi guys — thanks for discussing this trial!
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