Design, Setting, and Patients

The GRACE-VAP trial was a multicenter, open-label, noninferiority randomized clinical trial with blinded end point assessment that was conducted from April 1, 2018, through May 31, 2020. The trial protocol (provided in Supplement 1 and a protocol paper²⁰) was concordant with the Declaration of Helsinki²¹ and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan and was approved by the institutional review boards of Osaka General Medical Center and each of the participating institutions. Written informed consent was obtained from all participants or their representatives. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

The trial recruited patients from ICUs of 12 tertiary referral hospitals in Japan (Chukyo Hospital, Nagoya, Aichi; Ebina General Hospital, Ebina, Kanagawa; Hitachi General Hospital, Hitachi, Ibaraki; Kansai Medical University Hospital, Hirakata, Osaka; Kansai Medical University Medical Center, Moriguchi, Osaka; Nagasaki University Hospital, Nagasaki; Osaka General Medical Center, Osaka; Saga University Hospital, Saga; Sapporo City General Hospital, Sapporo, Hokkaido; Tajima Emergency and Critical Care Medical Center, Toyooka, Hyogo; University of the Ryukyus Hospital, Nakagami-gun, Okinawa; and Wakayama Medical University Hospital, Wakayama) (eTable 1 in Supplement 2). An independent data center and Data and Safety Monitoring Board provided trial oversight (eTable 2 in Supplement 2).

Patients were eligible if they were 15 years or older; had undergone mechanical ventilation for at least 48 hours; and had been diagnosed with VAP, defined as a modified Clinical Pulmonary Infection Score (mCPIS) of 5 or higher (score range: 0-10, with higher scores indicating greater likelihood of VAP).²² The exclusion criteria were known allergy to study medications, pregnancy, discharge from ICU, heart failure or atelectasis diagnosis, receipt of antibiotics for more than 24 hours after meeting the inclusion criteria, withdrawal or withholding of life support, or the discretion of the site investigator. We also excluded patients who were diagnosed with COVID-19 infection as an ex-post criterion when COVID-19 became pandemic in February 2020.

Data on race and ethnicity were not collected. It was presumed that only Japanese citizens would participate in the trial.