Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury

Abstract

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start.

Keywords: brain injury; cerebral hemorrhage; extremely preterm; neonate; recombinant human IGF-1.

Figure 1

Flowchart of infants included in the phase II study (9), the post-hoc analysis, and the subanalysis. GMH-IVH, germinal matrix hemorrhage and intraventricular hemorrhage; rhIGF-1, recombinant human insulin-like growth factor-1; rhIGFBP-3, recombinant human insulin-like growth factor binding protein-3. ^aOne infant had a serious adverse event with fatal outcome, but the primary reason for discontinuation was withdrawal of consent. ^bAll infants discontinued due to a serious adverse event with fatal outcome. ^cSeven of nine discontinuations were due to serious adverse events with fatal outcome. ^dFor the distribution analysis (n = 117), each infant was classified based on the maximum grade of GMH-IVH observed between day 0 and week 40 during a joint masked consensus review of all available scans for that infant; one infant receiving standard of care and three infants receiving rhIGF-1/rhIGFBP-3 died within 72 h of randomization and did not have an assigned maximum grade. ^eThe progression analysis (n = 104) was based on a comparison of longitudinal scans with the baseline grade 0 scan for each eligible infant; 17 infants were excluded for the progression analysis: grade 0 → missing (n = 3); grade I → grade I (n = 4); grade I → grade II (n = 2); grade II → grade II (n = 3); grade II → grade IV (n = 1); grade III → grade IV (n = 1); grade IV → grade IV (n = 1); missing → grade 0 (n = 1); missing → grade III (n = 1). Reprinted from Ley et al. (9), Copyright 2019, with permission from Elsevier. https://www.sciencedirect.com/science/article/pii/S0022347618315403.

Figure 2

Distribution of brain abnormalities among extremely preterm infants receiving rhIGF-1/rhIGFBP-3 or standard of care.^a GMH-IVH, germinal matrix hemorrhage and intraventricular hemorrhage; PHI, periventricular hemorrhagic infarction; PHVD, post-hemorrhagic ventricular dilatation; PVL, periventricular leukomalacia; rhIGF-1, recombinant human insulin-like growth factor-1; rhIGFBP-3, recombinant human insulin-like growth factor binding protein-3. ^aBased on the maximum-grade hemorrhage for each infant observed in cranial ultrasound on study days 0, 3, 7, 14, and 21, and at 40 weeks post-menstrual age.

Figure 3

Distribution of GMH-IVH grade II–III or PHI among infants assigned a maximum grade (n = 117), by treatment group and gestational age. GA, gestational age; GMH-IVH, germinal matrix hemorrhage and intraventricular hemorrhage; PHI, periventricular hemorrhagic infarction; rhIGF-1, recombinant human insulin-like growth factor-1; rhIGFBP-3, recombinant human insulin-like growth factor binding protein-3.

Figure 4

Brain injury severity score among infants assigned a maximum grade (n = 117), by treatment group. rhIGF-1 recombinant human insulin-like growth factor-1, rhIGFBP-3 recombinant human insulin-like growth factor binding protein-3.

Figure 5

Progression of GMH-IVH among infants with no evidence of GMH-IVH on cranial ultrasound at study entry (n = 104).^a GMH-IVH, germinal matrix hemorrhage and intraventricular hemorrhage; PHI, periventricular hemorrhagic infarction; rhIGF-1, recombinant human insulin-like growth factor-1; rhIGFBP-3, recombinant human insulin-like growth factor binding protein-3. ^aSeventeen infants were excluded for the progression analysis: grade 0 → missing (n = 3); grade I → grade I (n = 4); grade I → grade II (n = 2); grade II → grade II (n = 3); grade II → grade IV (n = 1); grade III → grade IV (n = 1); grade IV → grade IV (n = 1); missing → grade 0 (n = 1); missing → grade III (n = 1).