536 - Comparative Safety of LISA in Preterm Neonates with RDS: A Systematic Review and Meta-Analysis

Publication Number: 3517.536

Xuezheng Sun, Chiesi USA, Cary, NC, United States; Shaked Yarza, Chiesi USA, Cary, NC, United States; Yuting Kuang, IQVIA, San Mateo, CA, United States; Shruti Sharma, IQVIA, Gurgaon, Haryana, India; Jennifer Uyei, IQVIA, INC, San Mateo, CA, United States; Subhan Khalid, IQVIA, Wayne, PA, United States; Daniel Fuentes, Chiesi USA, Cary, NC, United States

Background: Less invasive surfactant administration (LISA) is increasingly used in preterm infants with respiratory distress syndrome (RDS). Understanding its safety profile compared to the INtubation-SURfactant-Extubation (INSURE) or endotracheal tube (ETT) techniques is essential to inform clinical practice.

Objective: To evaluate the safety profile of LISA compared to INSURE/ETT in preterm infants with RDS using evidence from randomized and non-randomized studies.

Design/Methods: A systematic literature review was conducted in MEDLINE, EMBASE, and CENTRAL to identify studies published between 2010 and 2024. Two types of analyses were performed: pairwise comparisons (LISA vs. INSURE/ETT), conducted in randomized controlled trials (RCTs) only, and arm-level pooled incidence of safety events across RCTs and non-randomized studies. All statistical analyses utilized Generalized Linear Mixed Models (GLMMs), with random-effects models to account for heterogeneity in study and patient characteristics. Subgroup analyses were conducted by gestational age (≤34 weeks), surfactant type, antenatal steroid exposure (≥50%), sedation and premedication use.

Results: A total of 19 RCTs (2,460 infants) and 26 non-randomized studies (2,360 infants) were identified for meta-analysis. Pairwise comparisons revealed no statistically significant differences between LISA and INSURE/ETT for most outcomes (Table 1), except for surfactant regurgitation/reflux (OR=2.29, 95%CI=1.21-4.33). Adverse event incidence rates among LISA patients were higher in non-randomized studies compared to RCTs (Table 2). Hypoxemia was the most frequently reported event across both treatment arms and study types (≥24%). Despite limitations in data availability, associations between LISA and safety outcomes in subgroups were consistent with those in the overall cohort. Notably, the Curosurf subgroup appeared to have a comparable or lower safety risk than the overall population.

Conclusion(s): To our knowledge, this is the first meta-analysis evaluating LISA safety outcomes across both randomized controlled trials and non- randomized studies. LISA consistently shows a safety profile comparable to INSURE/ETT for most outcomes. The higher incidence of adverse events in observational studies may reflect differences in outcome reporting and definitions; however, the possibility of improvement through training and standardized clinical procedures cannot be excluded.

Table 1. Overall cohort and subgroup analyses results for safety outcomes in RCTs, with pairwise comparison using random effects
Note: Results are presented as odds ratio [95% confidence interval] for LISA vs INSURE/ETT, where an odds ratio <1 favors LISA. A 95% CI that does not include 1 indicates a statistically significant difference between LISA and INSURE/ETT, as indicated by blue font.

# Number of studies for analysis represents the count of studies included in the base-case analysis as well as in various scenario analyses, which may vary depending on the outcome

* Studies with 0 events in both arms were not included in the analysis, and the total no. of studies including such studies are presented in parenthesis

** Only two RCTs used catheters specifically designed for LISA and none of them reported safety outcomes of interest for pairwise comparison, therefore sensitivity analysis was not feasible

Table 2. Summary results for arm-level pooled incidence of safety outcomes using random-effects model in RCTs and non-randomized studies
Note: Results of the arm-level pooled analysis are presented as incidence and 95% confidence interval, where incidence reflects the proportion of patients experiencing the safety event.

* For studies reporting multiple groups for LISA (e.g., different catheters), all eligible groups were included for analysis

** Assessment for safety outcomes with INSURE/ETT was not feasible in non-randomized studies due to lack of data

Abbreviations: ETT: Endotracheal Tube; INSURE: INtubation-SURfactant-Extubation; IVH: Intraventricular Haemorrhage; LISA: Less Invasive Surfactant Administration; PPV: Positive Pressure Ventilation; RCT: Randomized Controlled Trial.