Evaluation of Dobutamine Hydrochloride and Glucose Monohydrate in Septic Cardiomyopathy with Tissue Hypoperfusion: A Randomized Controlled Trial

The primary objective of this study is to evaluate the effects of adjunctive **Dobutamine** infusion versus placebo on organ failure in patients with fluid-filled septic shock who are stabilized under vasopressor support and have echocardiographically documented septic cardiomyopathy. This is clinically relevant as it aims to determine whether Dobutamine can improve outcomes in a critical care setting by potentially reducing organ failure in a population with high morbidity and mortality.

Secondary objectives include assessing the effects of Dobutamine versus placebo on various clinical parameters: - Evolution of indices of tissue hypoperfusion by Day 3 after randomization. - Requirement of organ function supports during ICU stay, reflecting underlying organ dysfunctions. - Systemic hemodynamics by Day 3 after randomization. - Incidence of severe cardiovascular adverse events during ICU stay. - Early mortality (Day-7), ICU mortality, and Day-28 mortality. - Days free from organ supports during ICU stay. - Lengths of ICU and hospital stay. - Left ventricular (LV) and right ventricular (RV) systolic and diastolic function assessed using echocardiography on Day 1.

The clinical trial involves a study population comprising **adult** patients aged 18 years and older, both male and female, who are hospitalized in the Intensive Care Unit (ICU). The participants are diagnosed with **septic shock** as per the Sepsis-3 definition, either upon ICU admission or during their stay. These individuals exhibit clinically suspected or documented acute infection leading to organ dysfunction, characterized by a change in the Sequential Organ Failure Assessment (SOFA) score of 2 or more points. They experience persistent hypotension despite adequate fluid resuscitation and require vasopressor support to maintain a steady mean arterial pressure of at least 65 mmHg. Additionally, participants have a lactate level greater than 2 mmol/L within the 24 hours preceding randomization. The trial specifically targets patients with septic cardiomyopathy, identified by an echocardiographically measured or visually assessed left ventricular ejection fraction of 40% or less, and a left ventricular outflow tract velocity-time integral of less than 14±1.5 cm, not related to persistent hypovolemia. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and informed consent is a prerequisite for participation.

The clinical trial is designed to evaluate the effects of **dobutamine hydrochloride** infusion compared to a placebo in patients with septic shock and echocardiographically documented septic cardiomyopathy. This study is a randomized, controlled, double-blind, multi-center trial. The trial aims to assess the impact of the intervention on organ failure in patients stabilized under vasopressor support. The trial is expected to last until September 2025, with participant recruitment having commenced in September 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (≥18 years), presence of septic shock as per the Sepsis-3 definition, and documented septic cardiomyopathy. Following randomization, participants will receive either the active treatment or placebo intravenously for a maximum treatment period of seven days. The primary endpoint is the evolution of a modified Sequential Organ Failure Assessment (SOFA) score from baseline to Day 3 post-randomization. Secondary endpoints include biological indices of tissue dysoxia, hemodynamic status, and severe cardiovascular adverse events, among others.

Study visits will include baseline assessments, followed by evaluations at 6 hours, Day 1, Day 2, and Day 3 after initiating the treatment. Additional follow-up visits will occur on Day 7, and assessments will continue through Day 28 and Day 90 to monitor all-cause mortality and other outcomes. The end-of-study visit will mark the conclusion of the participant's involvement in the trial. Participants are expected to be involved for the duration of the treatment period and follow-up assessments, with the possibility of early termination if adverse events or other conditions necessitate withdrawal from the study.

The clinical trial involves the administration of **dobutamine hydrochloride**, a chemical compound used as the experimental medication. Dobutamine hydrochloride is provided in a pharmaceutical form identified as PHF633. The medication is administered intravenously, with a maximum daily dose of 28,800 micrograms per kilogram and a total maximum dose of 201,600 micrograms per kilogram over a treatment period not exceeding seven days. The primary objective of this trial is to evaluate the effects of adjunctive dobutamine infusion on organ failure in patients with fluid-filled septic shock, who are stabilized under vasopressor support and have echocardiographically documented septic cardiomyopathy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes **glucose monohydrate** as a non-experimental treatment, serving as a placebo. This compound is provided in the form of a solution for infusion, specifically marketed as "GLUCOSE 5% AGUETTANT, solution pour perfusion" by Laboratoire Aguettant. The glucose solution is also administered intravenously, with the same dosing parameters as the experimental medication: a maximum daily dose of 28,800 micrograms per kilogram and a total maximum dose of 201,600 micrograms per kilogram over a maximum treatment period of seven days. The use of glucose monohydrate as a placebo allows for a controlled comparison to assess the efficacy of dobutamine hydrochloride in the specified patient population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the evaluation of the evolution of a modified Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score, excluding the neurologic system, from baseline (before randomization) to Day 1, Day 2, and Day 3 post-randomization. This score is a critical measure of organ failure in patients with septic shock.

Secondary endpoints include a range of biological, hemodynamic, and clinical parameters. Biological indices of tissue dysoxia will be measured at baseline, 6 hours after initiating **Dobutamine** or placebo, and on Days 1, 2, and 3. These indices include circulating lactate levels and central venous oxygen saturation (ScvO2), which serve as markers of tissue hypoperfusion and oxygen extraction, respectively. Hemodynamic status will also be assessed at these time points, with measurements of arterial pressure, heart rate, central venous pressure, cardiac index, and stroke volume using echocardiography or calibrated monitoring systems.

Additional secondary endpoints encompass the requirement for organ function supports during the ICU stay, such as the maximal dose and duration of open-labelled **Dobutamine** used as rescue therapy, vasopressor support, invasive mechanical ventilation, and renal replacement therapy. Severe cardiovascular adverse events, including hypotension, excessive sinus tachycardia, arrhythmias, acute coronary syndrome, and stroke, will be monitored. Mortality rates at Day-7, ICU discharge, Day-28, and Day-90, as well as the number of days free from vasopressor support, mechanical ventilation, and renal replacement therapy, will be recorded. The length of ICU and hospital stay will also be documented.

Echocardiographic assessments will be conducted at baseline and on Day 1, evaluating parameters such as left ventricular ejection fraction using the monoplane Simpson method, velocity-time integral of the left ventricular outflow tract Doppler, and various Doppler velocities and measurements related to cardiac function. These comprehensive assessments will provide a detailed evaluation of the efficacy of **Dobutamine** in the treatment of septic cardiomyopathy with tissue hypoperfusion.