Efficacy of Dexamethasone, Olanzapine, Hemodynamic Management, and Ventilation Strategies in Elective Cardiac Surgery: A Randomized Controlled Trial

The primary objective of this trial is to evaluate the **efficacy** of **dexamethasone** compared with placebo on the primary endpoint of days alive outside the hospital within 90 days in adult subjects undergoing elective or subacute isolated coronary artery bypass grafting (CABG), isolated aortic valve replacement (AVR), or CABG plus any concomitant valve surgery. The coprimary objectives include assessing the efficacy of **olanzapine** versus placebo administered preoperatively, the efficacy of flow-targeted versus pressure-targeted hemodynamic management during cardiopulmonary bypass (CPB), and the efficacy of low tidal volume ventilation versus no ventilation during CPB, on the same endpoint. These objectives are clinically relevant as they aim to improve postoperative outcomes and reduce hospital stay duration in patients undergoing cardiac surgery.

The secondary objectives of this trial are to determine the efficacy of the interventions on mortality and morbidity, assessed by either manifest organ damage or surrogate markers such as biomarkers of organ damage. Additionally, a pre-defined substudy will investigate cardiac CT images to explore graft patency, myocardial resting perfusion, and ventricular function three months post-surgery. This substudy will specifically assess graft patency and its predictors, associations between myocardial resting perfusion, graft patency, and outcomes, as well as predictors of left and right ventricular function.

The clinical trial involves a study population comprising **adult** subjects aged 18 years and older, who are scheduled for coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR), regardless of any additional concomitant valve surgery. Both male and female participants are included, and the trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals undergoing elective or subacute isolated CABG, isolated AVR, or CABG with any concomitant valve surgery. Participants' general health status, lifestyle considerations such as diet and physical activity, and specific inclusion or exclusion criteria beyond age and surgical scheduling are not detailed in the available data.

The clinical trial is designed to evaluate the efficacy of **dexamethasone** and **olanzapine** in reducing mortality and organ damage, as well as shortening the length of hospital stay in patients undergoing heart surgery, specifically coronary artery bypass grafting (CABG) and/or heart valve replacement. This trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The trial is expected to run from November 2022 to December 2028, with participants involved for a maximum treatment period of one day. The primary endpoint is the number of days participants are alive and outside the hospital within 90 days post-surgery. Secondary endpoints include time to occurrence of death, stroke, acute kidney injury, or heart failure, as well as severe post-operative complications, delirium, and quality of recovery scores.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being an adult over 18 years and scheduled for CABG and/or aortic valve replacement (AVR). Following the screening, participants will be randomly assigned to receive either the active treatment or placebo. The trial includes follow-up visits to monitor the participants' health status and collect data on the primary and secondary endpoints. The end-of-study visit will occur 90 days after surgery to assess the final outcomes. Participants may be terminated early from the study if they experience adverse events or if they withdraw consent. The trial aims to provide comprehensive data on the effectiveness of the interventions in improving post-surgical outcomes for cardiac surgery patients.

The clinical trial involves the administration of **Olanzapine Glenmark Europe 20 mg orodispersible tablets**. This experimental medication is formulated as an orodispersible tablet, designed for **oral use**. The active substance in this medication is **olanzapine**, a chemical compound classified under the ATC code N05AH03. The maximum daily dose is 10 mg, with a total treatment period of one day. The medication is manufactured by Glenmark Arzneimittel GmbH and is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in the study. The placebo is available in two pharmaceutical forms: a tablet for **oral use** and a solution for **intravenous use**. The oral placebo tablet is administered with a maximum daily dose of 10 mg, while the intravenous solution has a maximum daily dose of 20 mg. Both forms are chemically inert and are used to assess the efficacy of the experimental treatments by providing a baseline for comparison. The placebo is not a paediatric formulation and is administered for a maximum treatment period of one day.

Another experimental treatment in the trial is **Dexavit**, which contains the active substance **dexamethasone disodium phosphate**. This medication is provided as a solution for **intravenous use**. The maximum daily dose is 20 mg, and the treatment period is limited to one day. Dexavit is manufactured by Vital Pharma Nordic APS and is classified under the ATC code H02AB02. As with the other treatments, participant compliance with the administration schedule will be closely monitored to ensure adherence to the trial protocol.

The efficacy of the clinical trial titled "GLORIOUS II: Dexamethasone, olanzapine, flow-targeted versus pressure-targeted hemodynamic management, and low tidal volume ventilation in patients undergoing on-pump cardiac surgery – a multifactorial design randomized trial" will be assessed using specific primary and secondary endpoints. The primary endpoint is the number of days alive and outside the hospital within 90 days after surgery. This endpoint will be used to evaluate the efficacy of **dexamethasone** compared with placebo, as well as the efficacy of **olanzapine** versus placebo administered preoperatively. Additionally, the trial will assess the efficacy of flow-targeted versus pressure-targeted hemodynamic management during cardiopulmonary bypass (CPB) and the efficacy of low tidal volume ventilation versus no ventilation during CPB.

Secondary endpoints include the time in days to the occurrence of any component in a composite endpoint during follow-up, which consists of death from any cause, stroke, acute kidney injury, or new onset or worsening heart failure. Other secondary endpoints are severe post-operative complications during index admission, defined as a Clavien-Dindo class of 3 to 5, delirium during the first 7 days after surgery as measured by the Confusion Assessment Method for the ICU (CAM-ICU) or the Confusion Assessment Method (CAM) for general wards, and the Quality of Recovery-15 (QoR-15) score assessed 3 days after surgery. Additionally, 90-day outcomes such as survival, change in modified Rankin Scale (mRS) from baseline, health-related quality of life (EQ-5D-5L), change in self-perceived function, and days alive outside the ICU will be evaluated. The trial will also assess 180-day survival outcomes.