616 - Characterization of Cluster Randomized Clinical Trials in Neonatology

Publication Number: 2601.616

Marianna B. Castellanos, The Children's Hospital at Montefiore, Bronx, NY, United States; Susanne Hay, Harvard Medical School, Boston, MA, United States; Adrian Baca-Arzaga, University of Miami, Miami, FL, United States; Maria Laura Mourão, Beth Israel Deaconess Medical Center, Boston, MA, United States; Sofia Gnecco, Beth Israel Deaconess Medical Center, Brookline, MA, United States; Kim Ruiz-Arellanos, Beth Israel Deaconess Medical Center, Boston, MA, United States; Luna Hurtado-A, Beth Israel Deaconess Medical Center, Brighton, MA, United States; Santiago Reyes, Beth Israel Deaconess Medical Center, Boston, MA, United States; Grace E. Fuller, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States; Haresh Kirpalani, McMaster University Michael G. DeGroote School of Medicine, Burlington, ON, Canada; Roger F. Soll, University of VT, Burlington, VT, United States; Brian King, Harvard Medical School, Boston, MA, United States; John Zupancic, Harvard Medical School, Boston, MA, United States

Background: Most neonatal randomized controlled trials (RCTs) are individually randomized with small sample sizes, limiting evaluation of interventions at the unit or system level. Cluster RCTs allow enrollment of larger populations, evaluation of more complex interventions, and enhanced generalizability through multicenter collaboration. However, their use in neonatology has been scarce.

Objective: To characterize the prevalence and design characteristics of cluster vs non-cluster RCTs published between 2003-2022.

Design/Methods: We queried the NeoCanon database, a validated, comprehensive repository of neonatal RCTs. Trials published between 2003 and 2022 were included; and information including trial design (cluster or non-cluster), sample size, population characteristics (gestational age (GA) and birth weight (BW)), intervention studied, and study setting was extracted. Study characteristics were compared using chi-square Wilcoxon rank-sum. Temporal trends were evaluated using Poisson regression and logistic regression.

Results: Among 5319 neonatal RCTs, 2.4% (131) used a cluster design; however, they accounted for almost 80% (5.29 million out of 6.64 million) of total participants enrolled across studies. Seven cluster RCTs contributed 4.1 million participants. Cluster RCTs were most often multicenter and focused on programmatic or patient education intervention, whereas non-cluster RCTs more often evaluated drugs or devices. Cluster trials had substantially larger sample sizes (median 2312 [IQR 500-15123] vs. 80 [44-150]; p < 0.001). Reporting of positive results in the abstract did not differ between trial types (Table 1).  

Compared with non-cluster RCTs, cluster RCTs were more likely to have an unspecified GA (76% vs 32%). Specification of BW was low in both groups, but even less common among cluster RCTs (7% vs 23%). However, among the trials that reported this data, GA and BW did not differ significantly between the two groups. Cluster RCTs were more common in lower-income settings, while non-cluster RCTs predominated in higher-income settings.

The number of neonatal RCTs published per year increased between the study period (p < 0.001). However, the proportion of cluster RCTs did not change (p = 0.13), with a maximum of 25 cluster RCTs published in a single year (Figure 1).

Conclusion(s): Despite their potential advantages, cluster RCTs remain infrequent in neonatology. They differ from other RCTs, with larger sample sizes, use for different classes of interventions, and more frequent use in lower income settings. Why they are not more frequently used in higher income settings should be explored.

Figure 1. Annual trends in neonatal randomized controlled trial by study design
Figure 1 shows the annual number of published neonatal cluster and non-cluster RCTs from 2003-2022, demonstrating an overall increase in RCT publications over time, with cluster designs remaining less frequent.

Table 1. Characteristics of cluster versus non-cluster randomized controlled trials in neonatal research
Table 1 compares study design characteristics, intervention types, reporting practices, and study settings between cluster and non-cluster RCTs included in the NeoCanon database from 2003-2022.