Non-antibiotic Management in Acute Uncomplicated Diverticulitis (NAMAD)

BACKGROUND AND RATIONALE

Current guidelines from the American Gastroenterological Association (AGA) and the American Society of Colon and Rectal Surgeons (ASCRS) recommend selective rather than routine antibiotic use for acute uncomplicated diverticulitis. These recommendations are based primarily on four randomized trials conducted outside the United States: Antibiotic Therapy of Acute Uncomplicated Colonic Diverticulitis study (AVOD, Sweden, 2012 NCT01008488); Diverticulitis: Antibiotics or Close Observation? study (DIABOLO, Netherlands, 2017, NCT01111253); Selective Treatment with Antibiotics for Non-complicated Diverticulitis study (STAND, New Zealand/Australia, 2021, Australian clinical trials registration number: 12615000249550); and the Randomized Clinical Trial to Compare the Treatment of Mild Acute Diverticulitis With or Without Antibiotics (DINAMO) study (Spain, 2021, NCT02785549). Of these, only DINAMO evaluated a fully outpatient approach. No equivalent trial has been conducted in the United States, where antibiotic therapy remains routine for this patient population. Differences in patient demographics, comorbidity burden, healthcare delivery systems, and outpatient follow-up infrastructure may influence the generalizability of prior findings to U.S. populations, sustaining clinical equipoise.

HYPOTHESIS

In adults presenting to the Emergency Department (ED) with acute uncomplicated diverticulitis (modified Hinchey 0 or 1a) and meeting predefined low-risk criteria, outpatient management without antibiotics is non-inferior to standard outpatient antibiotic therapy with respect to diverticulitis-related hospitalization within 6 months.

STUDY DESIGN OVERVIEW

This is a prospective, single-center, open-label, randomized non-inferiority trial. Randomization will be performed in a 1:1 ratio using the REDCap randomization module with a pre-generated allocation table and concealed block sizes. Allocation will be automatically assigned by REDCap upon eligibility confirmation to ensure allocation concealment and reduce selection bias. Recruitment and follow-up will follow the Consolidated Standards of Reporting Trials (CONSORT) statement, including registration of all screened but non-enrolled patients with documented reasons for non-participation.

SETTING AND RECRUITMENT WORKFLOW

All patients presenting to the Emergency Department with signs and symptoms of acute diverticulitis and a CT scan of the abdomen and pelvis reporting acute diverticulitis will be clinically examined by the surgical residents involved in the study and screened for eligibility. Patients who achieve adequate symptom control during ED observation will be approached for informed consent and, if eligible and consenting, enrolled and randomized. Patients who do not achieve adequate symptom control within a maximum of 24 hours of ED observation will be admitted and will not enter the study.

Penicillin allergy status will be ascertained through electronic medical record review and participant self-report, including type of reaction and prior antibiotic tolerance. The study physician will reconcile available information to determine eligibility for the amoxicillin/clavulanate regimen versus the alternative regimen. No formal allergy testing will be performed.

FOLLOW-UP SCHEDULE

• In-person colorectal surgery clinic visit at 1-2 weeks post-enrollment
• Telephone follow-up at 4 weeks, 3 months, and 6 months

A standardized adverse event and symptom questionnaire will be administered at each follow-up timepoint, capturing pain control, gastrointestinal symptoms, fever, medication adherence, treatment- related adverse effects, healthcare utilization, and recurrence. Participants without response after 6 months of attempted contact will be classified as lost to follow-up.

SAMPLE SIZE CALCULATION

Assuming a complication rate of 1% with antibiotic therapy (AVOD) and a maximum acceptable complication rate of 5.8% in the non-antibiotic arm, with one-sided alpha = 0.05 and 80% power, 240 participants per arm are required. Accounting for an anticipated 20% dropout rate, the target enrollment is 278 participants per arm (total N = 556).

STATISTICAL ANALYSIS

Analyses will be performed on both intention-to-treat and per-protocol populations. Categorical variables will be compared using Pearson's chi-square test; continuous variables using independent-samples t-test or non-parametric equivalents as appropriate. Multivariable binary logistic regression will assess the association between baseline covariates and the occurrence of complications. Non-inferiority will be concluded if the upper bound of the one-sided 95% confidence interval for the between-group difference in the primary endpoint lies below the pre-specified non-inferiority margin of 5%. Two-sided alpha = 0.05 will be used for secondary analyses. All analyses will be performed using standard statistical software.

DATA AND SAFETY MONITORING

A formal Data and Safety Monitoring Plan will be implemented, with oversight by the Principal Investigator and an independent faculty monitor not involved in study enrollment or patient management. Monitoring will occur every 2 months and include assessment of recruitment, protocol adherence, data integrity, adverse events, unanticipated problems, complications, treatment failures, and hospitalizations. Interim safety analyses will be conducted periodically. Predefined stopping rules include a clinically or statistically significant excess of adverse outcomes in either arm compared to expected standards of care. Participants will be withdrawn from study interventions in the event of clinical deterioration, progression to complicated diverticulitis, systemic infection, inability to tolerate outpatient management, or at the treating physician's discretion based on safety concerns. Serious adverse events and unanticipated problems will be reported to the IRB and other appropriate institutional entities per institutional policy.

EXPECTED CONTRIBUTION

This study will generate the first prospective U.S.-based randomized evidence on the safety and effectiveness of non-antibiotic outpatient management of acute uncomplicated diverticulitis, informing clinical practice guidelines and antimicrobial stewardship efforts in this population.