Evaluation of Low-Dose Dobutamine and Tocilizumab in Acute Myocardial Infarction Patients at High Risk for Cardiogenic Shock: A Randomized, Double-Blind Trial

The primary objective of this study is to evaluate the effects of **dobutamine** infusion and/or a single post-percutaneous coronary intervention (PCI) intravenous dose of **tocilizumab** on plasma concentration of NT-proBNP. This serves as a proxy for assessing the development of hemodynamic instability or cardiogenic shock (CS) in patients with acute myocardial infarction (AMI) who present within 24 hours of chest pain and have an intermediate to high risk of CS, as determined by the ORBI risk score (≥11), but are not in overt shock at hospital admission. This is clinically relevant as it aims to identify potential therapeutic interventions that could mitigate the risk of CS, a severe complication of AMI.

The secondary objectives include determining the effects on:

• Development of in-hospital CS, in-hospital cardiac arrest, and/or transfer to the intensive care unit (ICU) during index admission
• Infarct size measured by cardiac magnetic resonance imaging (cMRI)
• Long-term all-cause mortality
• Biomarkers reflecting neurohormonal activation, endothelial function/damage, inflammation, connective tissue damage, and organ dysfunction
• PCI operators' post-procedure clinical assessment of the patient
• Development of non-cardiac arrest arrhythmia
• 2D echocardiographic findings of hemodynamics and left ventricular function
• Re-admission during the first year after index hospitalization, re-admission with heart failure, and re-infarction
• Sequential Organ Failure Assessment (SOFA) score
• Quality of life and mental and cognitive health at baseline and after three months

The clinical trial focuses on patients with **acute myocardial infarction** who are at an increased risk of developing cardiogenic shock. The study population includes both male and female participants, aged 18 years and older. Participants are required to have undergone revascularization with PCI and must present within 24 hours of experiencing chest pain. The trial population is selected based on an ORBI risk score of 10 or higher, indicating an intermediate to high risk of cardiogenic shock, although they are not in overt shock at hospital admission. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the effects of **dobutamine** infusion and a single dose of **tocilizumab** in patients with acute myocardial infarction at high risk of developing cardiogenic shock. The trial employs a 2x2 multifactorial design, ensuring rigorous control and randomization of participants to different treatment arms. The study aims to assess the impact of these interventions on plasma NTproBNP levels, serving as a proxy for hemodynamic instability. The trial is expected to run from February 14, 2022, to December 31, 2025, with participant involvement lasting up to one year, including follow-up assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as acute myocardial infarction, revascularization with PCI, and an ORBI risk score of 10 or higher. Following randomization, participants will receive the assigned treatment and be monitored for primary and secondary endpoints. Primary endpoints include NTproBNP levels from hospital admission to 48 hours post-admission. Secondary endpoints encompass a range of clinical and biomarker assessments, including infarct size, neurohormonal activation, and long-term outcomes like all-cause mortality and quality of life.

Study visits will include follow-up assessments during the index hospital admission and at three months post-admission, with additional evaluations for safety and efficacy. The end-of-study visit will occur at the conclusion of the one-year follow-up period. Participants may be withdrawn from the study if they experience adverse events, fail to comply with study procedures, or withdraw consent. The trial's design and procedures ensure comprehensive data collection to evaluate the therapeutic potential of the interventions in this high-risk patient population.

The clinical trial involves the administration of **Dobutamine**, marketed under the name Dobutrex, which is provided as a **solution for infusion**. This experimental medication is of chemical origin and is administered via **intravenous infusion**. The dosage is set at a maximum of 0.3 mg/kg/h, with the treatment period limited to one day. The administration of Dobutamine is intended to assess its effects on plasma concentration of NTproBNP in patients with acute myocardial infarction, particularly those at high risk of developing cardiogenic shock.

Another experimental medication used in the trial is **Tocilizumab**, marketed as RoActemra 20 mg/mL concentrate for solution for infusion. This biologically derived medication is also administered through **intravenous infusion**. The maximum daily and total dose is 280 mg, with a treatment period of one day. Tocilizumab is evaluated for its potential impact on hemodynamic stability in the same patient population.

The trial also includes a non-experimental treatment, Isoton (0.9%) NaCl, which serves as a placebo. This isotonic saline solution is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the specific treatment being administered. The placebo is administered in a manner consistent with the experimental treatments to maintain study integrity.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study design is a 2x2 multifactorial, double-blinded, randomized, placebo-controlled trial, which allows for the evaluation of the individual and combined effects of the experimental medications on the specified clinical outcomes.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the measurement of **NTproBNP** levels in blood samples collected from hospital admission to 48 hours post-admission. This biomarker serves as a proxy for the development of hemodynamic instability or cardiogenic shock in patients with acute myocardial infarction.

Secondary endpoints include a variety of parameters: infarct size as determined by cardiac MRI during the initial hospital stay and at a three-month follow-up, biomarkers indicative of neurohormonal activation, endothelial function or damage, inflammation (including IL-6 and C-reactive protein), connective tissue damage, and organ dysfunction. Additionally, 2D echocardiographic assessments of hemodynamics and left ventricular function, including strain measurements, will be conducted according to protocol. The SOFA score will be used to evaluate organ function, and the development of in-hospital cardiogenic shock, cardiac arrest, or ICU transfer will be monitored.

Long-term outcomes such as all-cause mortality, re-admission rates (both general and cardiovascular-specific), and re-admission due to heart failure or re-infarction within the first year post-hospitalization will also be evaluated. The trial will further assess the quality of life and mental and cognitive health at baseline and after three months. These efficacy parameters will be collected and analyzed at specified time points to determine the impact of the interventions on the patient population.