Effect of Dexmedetomidine vs Placebo on Cumulative Opioid Consumption in Premature Neonates Receiving Invasive Mechanical Ventilation: A Randomized Controlled Trial

The primary objective is to evaluate the effect of continuous intravenous infusion of dexmedetomidine compared to a placebo on the cumulative opioid doses, including both continuous infusions and boluses, in premature neonates undergoing invasive ventilation for a minimum of 24 hours. This assessment is clinically relevant to determine if dexmedetomidine can reduce the total requirement for opioid analgesia in this population. The secondary objectives aim to evaluate efficacy and safety through the following parameters:

• Percentage of time spent in an appropriate comfort/analgesia state according to the COMFORTneo scale.
• Duration of invasive ventilation during the studied episode.
• Frequency of opioid-related adverse effects.
• Cumulative dose of benzodiazepines and the total number of days requiring opioids or benzodiazepines.
• Frequency of muscle blocker use.
• Rates of reintubation within 7 days after the first planned extubation and the rate of unplanned extubations.
• Frequency and severity of hemodynamic adverse events.
• Frequency of opioid withdrawal syndrome as measured by the Finnegan score.
• In-hospital mortality.
• Total duration of invasive and non-invasive ventilation during hospital stay.
• Total duration of NICU and hospital stay.
• Severe neonatal morbidity at 36 weeks postmenstrual age and at hospital discharge.
• Neurodevelopment at ages 2 and 6 years.

The sponsor did not provide information regarding the total number of participants. The study population consists of premature neonates who are vulnerable and include both males and females. Participants are characterized by neonatal respiratory distress and associated pain. Inclusion requires a gestational age at birth of less than 32 weeks and a corrected gestational age of less than 32 weeks postmenstrual age. Eligible subjects must be undergoing mechanical ventilation for an expected or effective duration of more than 24 hours, with a duration of ventilation lasting less than 72 hours at the time of inclusion.

This Phase III, multicenter, randomized, double-blind, controlled trial is designed to evaluate the efficacy of dexmedetomidine compared to a placebo in premature neonates undergoing invasive ventilation. The study focuses on infants with a gestational age under 32 weeks who require mechanical ventilation for an expected duration exceeding 24 hours. Participants will receive either a continuous intravenous infusion of dexmedetomidine or a glucose placebo. The primary objective is to assess the impact of the intervention on the cumulative dose of opioids, including morphine, sufentanil, and fentanyl, converted to morphine equivalents. Secondary endpoints include assessments of pain and discomfort, opioid-related adverse effects, dexmedetomidine tolerance, safety outcomes at discharge, and long-term neurodevelopment. The study period for evaluating the primary endpoint spans from the initiation of the investigational drug until the cessation of all opioids or the investigational drug for at least 24 hours. Recruitment is estimated to occur between February 2026 and February 2034.

The experimental treatment consists of dexmedetomidine, provided as a solution for infusion. The administration involves an intravenous infusion at a dosage of 24 µg/kg.

The control group receives a placebo consisting of glucose 5% in a solution for infusion. This is administered via intravenous infusion at a dose of 1.2 g.

The primary efficacy endpoint is the cumulative dose of opioids, including morphine, sufentanil, and fentanyl, converted to an equivalent morphine dose in µg/kg. This measurement is calculated using fixed equipotency ratios based on national prescription habits during the period from the initiation of the investigational drug until the cessation of all opioids or the investigational drug for at least 24 hours.

Secondary efficacy parameters include:

• Pain and comfort outcomes, assessed using the COMFORTneo pain and comfort scale, the number of days requiring opioids or benzodiazepines, the cumulative dose of midazolam, and the frequency of muscle blocker use.
• Opioid adverse effects, including age at full enteral feeding, urinary retention, the Finnegan neonatal withdrawal scale, duration of invasive ventilation, extubation failure at 3 and 7 days post-extubation, and unplanned extubation.
• Dexmedetomidine tolerance, evaluated by bradycardia, hypotension, and the use of anti-hypotensive treatments.
• Safety outcomes at discharge, such as in-hospital mortality, total duration of ventilation, duration of NICU and hospital stay, intraventricular hemorrhage, periventricular leukomalacia, sepsis, patent ductus arteriosus, bronchopulmonary dysplasia at 36 weeks postmenstrual age, necrotizing enterocolitis, intestinal perforation, and retinopathy of prematurity.
• Long-term neurodevelopment, measured via the Parent Report of Children's Abilities-Revised at age 2 and the computerized Adaptable Test Battery at age 6.