Comparative Efficacy of Dexmedetomidine Versus Midazolam on Extubation Time in Mechanically Ventilated Very Preterm Neonates: A Randomized Controlled Trial

The primary objective of this study is to compare the **efficacy** of dexmedetomidine-based sedation versus midazolam-based sedation in very preterm neonates. This is clinically relevant as it aims to determine the most effective sedation method for improving extubation outcomes in this vulnerable population, potentially reducing the duration of mechanical ventilation and associated complications.

Secondary objectives include evaluating the use of adjuvant anesthetic agents, including opioids, between inclusion and extubation; assessing the quality of sedation; monitoring extubation failure 24 hours post-extubation; identifying withdrawal syndrome as indicated by a Finnegan score greater than 8; observing hemodynamic and respiratory adverse effects from inclusion to 84 hours after treatment discontinuation; and examining in-hospital morbidity and mortality. These objectives are crucial for understanding the broader implications of sedation choice on patient safety and recovery.

The clinical trial involves a study population of **very preterm neonates** with a gestational age at birth of less than 32 weeks and a corrected gestational age of less than 45 weeks. The trial includes both male and female subjects, and the participants are considered a vulnerable population due to their age and health status. The sponsor has not provided the total number of participants. The trial population was selected based on specific criteria, including admission to the NICU and the need for sedation in the context of invasive mechanical ventilation. Participants must not have any concomitant use of curare agents, previous extubation within 7 days, Clonidine treatment, hemodynamic instability, or be under palliative care. The study aims to compare the efficacy of dexmedetomidine-based sedation versus midazolam-based sedation in this specific group of neonates.

The clinical trial is designed to evaluate the **efficacy** of dexmedetomidine-based sedation compared to midazolam-based sedation in very preterm neonates requiring sedation for invasive mechanical ventilation. This is a Phase III, multicenter, randomized, controlled, double-blind trial. The trial aims to assess the time-to-extubation after discontinuation of the sedative agents as the primary endpoint. Secondary endpoints include the administration of opioid agents, time to achieve a normal Comfort B score, intubation rate at 24 hours post-extubation, and the occurrence of hemodynamic and respiratory adverse events, among others.

The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as gestational age at birth less than 32 weeks and corrected gestational age less than 45 weeks. Participants must not have any contraindications related to the administration of dexmedetomidine or midazolam, and must not be receiving palliative care or have hemodynamic instability. Following the screening, participants will be randomized to receive either dexmedetomidine or midazolam, administered intravenously. The maximum treatment period is 14 days, with follow-up visits scheduled to monitor the primary and secondary endpoints. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any adverse events.

The expected duration of participant involvement is up to 14 days, with conditions for early termination including the development of medical contraindications, withdrawal of consent, or significant adverse events. The trial is estimated to start recruitment in March 2025 and conclude by June 2029. Participants will be closely monitored throughout the study to ensure safety and adherence to the protocol. The trial's design and procedures are structured to provide robust data on the comparative efficacy of the two sedation strategies in this vulnerable population.

The clinical trial involves the administration of **DEXMEDETOMIDINE EVER PHARMA 100 microgrammes/mL**, a **solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous administration. The dosing regimen for dexmedetomidine is calculated based on body weight, with a maximum daily dose of 4.8 µg/kg and a maximum total dose of 67.2 µg/kg over a treatment period not exceeding 14 days. The solution is diluted for infusion and administered intravenously, ensuring precise control over the sedation levels in the study participants. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

**MIDAZOLAM** is used as a comparator treatment in this study. It is provided as a **solution for injection** and is administered via intravenous perfusion. The dosing for midazolam is also weight-based, with a maximum daily dose of 960 µg/kg and a maximum total dose of 13,440 µg/kg over a 14-day period. Midazolam serves as the standard-of-care therapy against which the efficacy of dexmedetomidine is compared. The administration of midazolam is carefully monitored to maintain consistent sedation levels and ensure participant safety throughout the trial.

The efficacy of dexmedetomidine-based sedation versus midazolam-based sedation in very preterm neonates will be assessed in this randomized controlled multicenter trial. The primary endpoint for evaluating efficacy is the **time-to-extubation** after discontinuation of the sedative agents. This will provide a direct measure of the effectiveness of each sedation method in facilitating extubation in the target population.

Secondary endpoints include several parameters to further assess the efficacy and safety of the sedation methods. These include the administration of opioid agents during the treatment period, the time in hours between the start of sedation and achieving a normal Comfort B score (between 11 and 17), and the intubation rate at 24 hours post-extubation. Additionally, the proportion of patients with at least one Finnegan score greater than 8 within three days after extubation will be recorded. Hemodynamic and respiratory adverse events, such as bradycardia, hemodynamic instability, desaturation below 85% despite optimized mechanical ventilation, and reintubation, will also be monitored. In-hospital mortality and severe neonatal morbidity are included as secondary endpoints to ensure comprehensive safety and efficacy evaluation.