Randomized Controlled Trial of Prophylactic Versus Selective Less Invasive Surfactant Administration in Preterm Infants with Respiratory Distress Syndrome Using Phospholipid Fraction, Bovine Lung, and Poractant Alfa

The primary objective of this study is to determine whether the **prophylactic** administration of surfactant in preterm infants, specifically those with a gestational age ranging from 25 weeks + 0 days to 30 weeks + 6 days, results in an improved forced expiratory volume within the first second (**FEV1**) at the age of 5 years. This is clinically relevant as it addresses the potential long-term respiratory benefits of early surfactant intervention in infants at risk of **respiratory distress syndrome**, a common and serious condition in preterm infants.

Secondary objectives include the investigation of the influence of prophylactic **Less Invasive Surfactant Administration** (LISA) therapy on long-term lung function and complications associated with prematurity. These objectives aim to provide a comprehensive understanding of the broader impacts of early surfactant therapy beyond immediate respiratory outcomes, potentially guiding future clinical practices in neonatal care.

The clinical trial focuses on **respiratory distress syndrome in preterm infants**. The study population comprises both male and female preterm infants with a gestational age ranging from 25 weeks + 0 days to 30 weeks + 6 days. The trial includes infants who are spontaneously breathing on CPAP, with a pulse oximetrically measured saturation of at least 90% and a FiO2 of 30% or less. Participants are required to be 60 minutes old or younger at the time of inclusion. The trial population is considered vulnerable due to the age and health status of the participants. The sponsor has not provided information regarding the total number of participants. Selection criteria include obtaining written informed consent from the legal guardian(s), which can be done retrospectively if necessary. The study does not specify any particular lifestyle considerations such as diet or physical activity, given the age and condition of the participants.

The clinical trial is a **randomized controlled trial** designed to evaluate the efficacy of prophylactic versus selective "Less Invasive Surfactant Administration" in preterm infants diagnosed with **respiratory distress syndrome**. The study is structured as a prospective, controlled, parallel-group, single-blinded, multicenter national trial. Participants will be randomly assigned in a 50:50 ratio to either the intervention or control group. The primary objective is to determine if prophylactic surfactant administration improves the forced expiratory volume within the first second (FEV1) at the age of five years. The trial is expected to conclude by July 31, 2029, with recruitment having commenced on February 15, 2022.

Study visits are sequenced to ensure comprehensive data collection and participant safety. The initial visit, known as the inclusion or screening visit, involves assessing eligibility criteria, which include a gestational age of 25+0 to 30+6 weeks, age less than or equal to 60 minutes, spontaneous breathing on CPAP, and a pulse oximetrically measured saturation of 90% or higher with a FiO2 of 30% or less. Written informed consent from the legal guardian(s) is required. Follow-up visits will be scheduled to monitor the participants' health and collect data on secondary endpoints, such as FVC z-score, FEV1/FVC z-score, and other developmental assessments at the age of five years. The end-of-study visit will finalize data collection and assess the primary endpoint.

Participant involvement is expected to last until the child reaches five years of age, with regular follow-up assessments. Conditions that may lead to early termination from the study include withdrawal of consent by the legal guardian(s) or any adverse events that compromise the safety of the participant. The trial aims to demonstrate the superiority of the intervention in improving long-term respiratory outcomes in preterm infants.

The clinical trial involves the administration of two experimental medications, both designed for **endotracheopulmonary instillation** in the form of a suspension. The first medication, **ALVEOFACT®**, is a preparation consisting of a powder and solvent to create a suspension. It contains the active substance **phospholipid fraction, bovine lung**. The pharmaceutical form is specifically for endotracheopulmonary use, and the medication is administered as a suspension. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 200 mg/kg and a total maximum dose of 100 mg/kg. The treatment period is limited to one day. The medication is not a pediatric formulation and is not classified as an orphan drug. Compliance with the dosing schedule is monitored throughout the trial.

The second experimental medication is **Curosurf®**, which is also a suspension for endotracheopulmonary instillation. The active substance in Curosurf® is **poractant alfa**, a mixture used for the same route of administration as ALVEOFACT®. The dosage regimen mirrors that of ALVEOFACT®, with a maximum daily dose of 200 mg/kg and a total maximum dose of 100 mg/kg, administered over a single day. Similar to ALVEOFACT®, Curosurf® is not formulated specifically for pediatric use and is not designated as an orphan drug. Participant compliance with the administration protocol is carefully monitored to ensure adherence to the study's dosing requirements.

Both medications are utilized in the context of a randomized controlled trial aimed at evaluating the prophylactic versus selective administration of surfactant in preterm infants. The trial's objective is to determine the impact of these treatments on the forced expiratory volume within the first second (FEV1) at the age of five years in infants born between 25 weeks + 0 days and 30 weeks + 6 days of gestation. No non-experimental treatments, such as standard-of-care therapy or placebo, are mentioned in the trial protocol.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the improvement in **forced expiratory volume within the first second (FEV1)** at the age of 5 years, measured using the Global Lung Function Initiative z-score. Secondary endpoints include several parameters evaluated at the age of 5 years: the FVC z-score, FEV1/FVC z-score, walking distance in the 3-minute walk test, incidence of obstructive bronchitis treated with medication in the last 12 months, presence of cerebral palsy as defined by Gross Motor Function Classification System values greater than 1, scores from the Movement Assessment Battery for Children, and intelligence quotient determined with the WPPSI IV.

The trial is designed as a prospective, randomised, controlled, parallel-group, single-blinded, multicentre, national study. Participants will be randomly assigned to either the intervention or control group in a 50:50 ratio. The primary objective is to demonstrate the superiority of the intervention in improving the primary endpoint. The trial will include preterm infants with a gestational age of 25 weeks + 0 days to 30 weeks + 6 days, who are spontaneously breathing on CPAP with a pulse oximetrically measured saturation of at least 90% and a FiO2 of 30% or less. Written informed consent from the legal guardians is required for participation.