Early Sedation with Dexmedetomidine vs. Placebo in Older Ventilated Critically Ill Patients

The primary objective of this study is to evaluate **mortality** among critically ill patients aged 65 years and older who are administered early sedation with **dexmedetomidine** (DEX) as the primary sedative agent. This objective aims to verify the findings of the sub-group analysis in the SPICE III trial, which compared early sedation with dexmedetomidine to usual care in critically ill patients. The clinical relevance of this objective lies in its potential to inform sedation practices in older patients, potentially improving survival outcomes in this vulnerable population.

Secondary objectives include:

• Comparing other key clinical outcomes of early sedation with DEX versus placebo in patients aged 65 years and older.
• Exploring possible mechanistic explanations for the observed effects in older patients as noted in the SPICE III study.

The clinical trial involves a total of **2500 participants** who are critically ill patients requiring high-level medical care, including mechanical ventilation, vasopressors, and sedative/analgesic medication. The study population consists of individuals aged **65 years and older**, encompassing both male and female subjects. Participants were selected based on their critical health status, specifically those who are intubated and receiving invasive mechanical ventilation in an intensive care unit. The trial includes a vulnerable population, as these patients require immediate and ongoing sedative medication for comfort, safety, and to facilitate the delivery of life support measures. The selection criteria ensure that the treating clinicians believe the patients will remain intubated and ventilated until at least the day after tomorrow, indicating a significant need for continued intensive care.

The clinical trial is designed to evaluate the efficacy of **dexmedetomidine** as an early sedative agent compared to a placebo in critically ill patients aged 65 years and older who are dependent on mechanical ventilation. This is a randomized, double-blind, controlled trial with a primary objective to assess 90-day all-cause mortality. Secondary endpoints include the number of days alive and free of coma and delirium at 28 days, the number of days alive and ventilator-free at 28 days, major adverse kidney events at 28 days, duration of mechanical ventilation in survivors, and hospital length of stay in survivors. The trial is categorized as a Phase IV study, with both the investigational product and placebo having marketing authorization in the concerned Member States. The trial is expected to run from August 2023 to December 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 65 years), current intubation, and the need for ongoing sedative medication. Follow-up visits will be conducted to monitor the participants' health status and collect data on the primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any adverse events. The expected length of participant involvement is up to 4 days, corresponding to the maximum treatment period with the investigational product. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

The clinical trial involves the administration of **Dexmedetomidine EVER Pharma 100 micrograms/ml concentrate for solution for infusion**. This experimental medication is provided in the form of a concentrate intended for solution for infusion. The route of administration is via **infusion**, with a maximum daily dose of 9.6 micrograms per kilogram and a total maximum dose of 268 micrograms per kilogram. The treatment period is limited to a maximum of 4 days. The pharmaceutical product is manufactured by EVER VALINJECT GMBH and is authorized under the marketing authorization number PL 46654/0005. The medication is classified under the ATC code N05CM18. The trial aims to evaluate the efficacy of early sedation with dexmedetomidine in critically ill patients aged 65 years and older.

The study also includes a **placebo** control, which consists of 2 ml of saline solution. This placebo is manufactured by EVER Pharma, adhering to the same Good Manufacturing Practice (GMP) standards as the experimental medication. The placebo is used to provide a comparator for the experimental treatment, ensuring the validity of the trial results. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the effects of the experimental medication.

Efficacy in the clinical trial titled "Early Sedation with Dexmedetomidine vs. Placebo in Older Ventilated Critically Ill Patients" will be assessed using both primary and secondary endpoints. The primary endpoint is the 90-day all-cause mortality rate. Secondary endpoints include the number of days alive and free of coma and delirium at 28 days, the number of days alive and ventilator-free at 28 days, the occurrence of Major Adverse Kidney Events at 28 days, the duration of mechanical ventilation in survivors, and the hospital length of stay in survivors. These endpoints will be measured and collected at specified timepoints, such as 28 days and 90 days, using validated clinical assessments and patient records. The analysis will focus on comparing the outcomes between the group receiving **Dexmedetomidine** and the placebo group to determine the efficacy of early sedation with Dexmedetomidine in the specified patient population.