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

Sandra Horsch; Alessandro Parodi; Boubou Hallberg; Mariya Malova; Isabella M Björkman-Burtscher; Ingrid Hansen-Pupp; Neil Marlow; Kathryn Beardsall; David Dunger; Mirjam van Weissenbruch; Lois E H Smith; Mohamed Hamdani; Alexandra Mangili; Norman Barton; Luca A Ramenghi; Ann Hellström; David Ley; ROPP-2008-01 Study Team

doi:10.3389/fped.2020.517207

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

Front Pediatr. 2020 Oct 9:8:517207. doi: 10.3389/fped.2020.517207. eCollection 2020.

Authors

Sandra Horsch^{1

2}, Alessandro Parodi³, Boubou Hallberg², Mariya Malova³, Isabella M Björkman-Burtscher^{4

5}, Ingrid Hansen-Pupp⁶, Neil Marlow⁷, Kathryn Beardsall⁸, David Dunger⁸, Mirjam van Weissenbruch⁹, Lois E H Smith¹⁰, Mohamed Hamdani¹¹, Alexandra Mangili¹², Norman Barton¹¹, Luca A Ramenghi^{3

13}, Ann Hellström¹⁴, David Ley⁶; ROPP-2008-01 Study Team

Affiliations

¹ HELIOS Klinikum Berlin-Buch, Berlin, Germany.
² Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
³ Neonatal Intensive Care Unit, Department Mother and Child, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Giannina Gaslini, Genoa, Italy.
⁴ Department of Clinical Sciences Lund, Radiology, Skåne University Hospital, Lund University, Lund, Sweden.
⁵ Clinical Sciences, Radiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
⁶ Department of Clinical Sciences Lund, Pediatrics, Skåne University Hospital, Lund University, Lund, Sweden.
⁷ Department of Academic Neonatology, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
⁸ Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
⁹ Department of Pediatrics, Division of Neonatology, Vrije Universiteit University Medical Center, Amsterdam UMC, Amsterdam, Netherlands.
¹⁰ Harvard Medical School, Boston Children's Hospital, Boston, MA, United States.
¹¹ Global Clinical Development, Rare Metabolic Diseases, Shire, a Takeda Company, Lexington, MA, United States.
¹² Global Clinical Development, Rare Metabolic Diseases, Shire, a Takeda Company, Zurich, Switzerland.
¹³ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.
¹⁴ Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.

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.

Copyright © 2020 Horsch, Parodi, Hallberg, Malova, Björkman-Burtscher, Hansen-Pupp, Marlow, Beardsall, Dunger, van Weissenbruch, Smith, Hamdani, Mangili, Barton, Ramenghi, Hellström, Ley and the ROPP-2008-01 Study Team.

Abstract

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