Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomized clinical trial

IntroductionAntibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as anti-pseudomonal cephalosporins and penicillins. However, in observational studies some anti-pseudomonal cephalosporins (e.g. cefepime) is associated with neurologic dysfunction while the most common anti-pseudomonal penicillin (piperacillin-tazobactam) is associated with acute kidney injury. No randomized control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of anti-pseudomonal cephalosporins and anti-pseudomonal penicillins among acutely ill patients receiving empiric antibiotics. Methods and AnalysisThe Antibiotic Choice On ReNal outcomes (ACORN) trial is a prospective, single-center, non-blinded randomized trial being conducted at Vanderbilt University Medical Center. The trial will enroll 2,500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomized 1:1 to receive cefepime or piperacillin-tazobactam upon first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of acute kidney injury and death occurring between enrollment and 14 days after enrollment. This will be compared between patients randomized to cefepime and randomized to piperacillin-tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are Major Adverse Kidney Events through day 14 and number of days alive and free of delirium and coma in 14 days after enrollment. Enrollment began on November 10, 2021 and is expected to be completed in December 2022. Ethics and DisseminationThe trial was approved by the Vanderbilt University Medical Center institutional review board with a waiver of informed consent. Results will be submitted in a peer-reviewed journal and presented at scientific conferences. Trial RegistrationThis trial was registered with ClinicalTrials.gov (NCT05094154) on October 26, 2021, prior to enrollment of the first patient on November 10, 2021. Strengths and LimitationsO_LIThis ongoing pragmatic trial will compare the effects of cefepime vs piperacillin-tazobactam on acute kidney injury and death among acutely ill adults receiving gram-negative antibiotic therapy in the Emergency Department or Intensive Care Unit. C_LIO_LIStrengths: Broad eligibility criteria, inclusion of a range of indications for antibiotic therapy, and use of the electronic health record to screen for eligible patients and facilitate delivery of the assigned intervention will increase the external validity of the findings C_LIO_LILimitations: After concealed randomization, patients, clinicians, and investigators are unblinded to study group assignment. Because urine output is not systematically available across all care, the outcome of AKI is based on creatinine measurements. C_LI