Evaluation of Propofol Sedation Versus Placebo in Less Invasive Surfactant Administration for Respiratory Distress Syndrome in Preterm Infants <32 Weeks Gestation

The primary objective of this clinical trial is to evaluate the efficacy of **propofol** sedation compared to placebo during the Less Invasive Surfactant Administration (LISA) procedure in preterm infants born at less than 32 weeks of gestational age. The trial aims to determine whether sedation with propofol is non-inferior to placebo in terms of the need for mechanical ventilation within the first 72 hours of life. This is clinically relevant as it addresses the management of Respiratory Distress Syndrome in this vulnerable population, potentially impacting the standard of care and improving neonatal outcomes.

Secondary objectives include:

• Comparing sedation by propofol versus placebo during the LISA procedure, specifically evaluating the need for mechanical ventilation within 72 hours of life across different gestational age classes (<28 weeks, 28-31 weeks).
• Assessing comfort and pain reduction in the intervention group compared to the control group during and one hour after the LISA procedure.
• Evaluating the rate of ketamine administration for rescue in each group.
• Assessing the quality conditions of the procedure, including per-procedure events (tolerance) and clinician satisfaction (efficacy) during the LISA procedure.
• Evaluating the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks of gestational age.
• Assessing in-hospital neonatal morbidity and mortality.
• Evaluating the neurodevelopmental outcomes at two years corrected age among survivors.

The clinical trial involves a study population of **preterm infants** born at less than 32 weeks of gestational age, both male and female, who are experiencing **Respiratory Distress Syndrome** (RDS) within the first 48 hours of life. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are required to be treated with Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPAP) and must require surfactant therapy. The trial population was selected based on specific inclusion criteria, including the need for a certain level of oxygen support and the availability of an intravenous line. All participants must be covered by French Social Security and have a signed informed consent form. The study does not focus on a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are relevant to this trial.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the respiratory effects of the Less Invasive Surfactant Administration (LISA) method with sedation by **propofol** versus the absence of sedation in preterm infants. The primary objective is to assess the need for mechanical ventilation (MV) within 72 hours of life in preterm babies born at less than 32 weeks of gestational age, who present with **Respiratory Distress Syndrome** (RDS). The trial is set to run from October 7, 2019, to April 30, 2026, with recruitment having started on October 31, 2019, and expected to end by March 30, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as gestational age, presence of RDS, and the need for surfactant treatment. The trial will include follow-up visits to monitor the primary endpoint, which is the rate of MV from the start of the LISA procedure up to 72 hours of life. Secondary endpoints include the rate of MV in different gestational age classes, the Faceless Acute Neonatal Scale (FANS) assessment during LISA, and the rate of **ketamine** administration for rescue. The end-of-study visit will evaluate long-term outcomes such as bronchopulmonary dysplasia (BPD) at 36 weeks of gestational age and in-hospital neonatal morbidity and mortality.

Participant involvement is expected to last until the completion of the study, with specific conditions outlined for early termination, such as withdrawal of consent or adverse events. The trial will ensure that all procedures adhere to ethical standards, with informed consent obtained from the guardians of the preterm infants. The study aims to provide valuable insights into the efficacy and safety of sedation during the LISA procedure, potentially influencing future clinical practices for managing RDS in preterm infants.

The clinical trial involves the administration of **MEDIALIPIDE 20 POUR CENT**, an emulsion for infusion, which contains the active substances **triglycerides, medium chain** and **soya oil**. This pharmaceutical product is provided in the form of an emulsion for infusion and is administered via **intravenous use**. The product is manufactured by B.BRAUN MEDICAL SAS and is utilized as part of parenteral nutrition. The emulsion is not a pediatric formulation and is classified under the ATC code B05BA02, indicating its use as a fat emulsion.

**KETAMINE RENAUDIN 10 mg/ml**, a solution for injection, is another treatment used in the trial. The active substance in this product is **ketamine hydrochloride**, and it is administered intravenously. This solution is produced by LABORATOIRE RENAUDIN and serves as an anesthetic. The product is not formulated for pediatric use and is categorized under the ATC code N01AX03, which corresponds to ketamine.

The trial also includes the use of **PROPOFOL LIPURO 1% (10 mg/ml)**, an emulsion for injection or infusion. The active substance is **propofol**, and it is administered through intravenous administration. Manufactured by B.BRAUN MELSUNGEN AG, this product is used as an anesthetic. It is not a pediatric formulation and is classified under the ATC code N01AX10, which pertains to propofol. The administration of these treatments is monitored to ensure participant compliance with the dosing schedules.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of mechanical ventilation (MV) from the start of the Less Invasive Surfactant Administration (LISA) procedure up to 72 hours of life in each group. Secondary endpoints include the rate of MV within the same timeframe for each gestational age class (<28 weeks, 28-31 weeks), the **Faceless Acute Neonatal Scale (FANS)** assessed during the LISA procedure, the rate of ketamine administration for rescue, quality conditions, assessment of bronchopulmonary dysplasia (BPD) at 36 weeks gestational age, in-hospital neonatal morbidity and mortality, and at two years, the Ages and Stages Questionnaire (ASQ), Gross Motor Function Classification Scale in cases of motor impairment, and visual and hearing function.

The FANS is a validated scale that evaluates behavioral items such as limb movements and vocal expression, as well as physiological items like heart rate variation, bradycardia, or desaturation, on a scale from 0 (no pain) to 10 (maximal pain). The trial will involve a double-blind, non-inferiority design comparing sedation by propofol versus placebo during the LISA procedure in preterm infants less than 32 weeks of gestational age. The need for MV within 72 hours of life will be a critical measure of efficacy. Data collection will occur at specified timepoints, and the analysis will focus on comparing the outcomes between the propofol and placebo groups to determine the efficacy of sedation in reducing the need for MV.