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

Abstract

Introduction: Antibiotics 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 Analysis: The 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 Dissemination: The 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 Registration: This trial was registered with ClinicalTrials.gov (NCT05094154) on October 26, 2021, prior to enrollment of the first patient on November 10, 2021.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT05094154

Funding Statement

The project described was supported by the VICTR Learning Healthcare System Platform under CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. It contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. E.T.Q. was supported by the National Heart, Lung, and Blood Institute award No. T32HL087738. J.D.C. was supported in part by the NHLBI (K23HL153584). M.W.S. was supported in part by the NHLBI (K23HL143053). E.D.S. was supported by the Vanderbilt OBrien Kidney Center P30-DK114809 for service provided through the Clinical and Translational Research Core. The funding institutions had no role in (1) conception, design, or conduct of the study, (2) collection, management, analysis, interpretation, or presentation of the data, or (3) preparation, review, or approval of the manuscript.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of Vanderbilt University Medical Center gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produce in the present work are contained in the manuscript

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