rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

Abstract

Objective: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants.

Study design: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 23^0/7 weeks to 27^6/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 µg/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 29^6/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 40^4/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28-109 µg/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures.

Results: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures.

Conclusions: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage.

Trial registration: ClinicalTrials.gov: NCT01096784.

Keywords: bronchopulmonary dysplasia; intraventricular hemorrhage; neonatology; retinopathy of prematurity.

Figure 1.

A, Study design and B, patient disposition. *Informed consent was obtained before birth or within 24 hours after birth. † One infant had an SAE with a fatal outcome, but the primary reason for discontinuation was withdrawal of consent. ‡ All infants discontinued owing to an SAE with fatal outcome. § Seven of 9 discontinuations were owing to SAEs with fatal outcome.

Figure 2.

Mean (SD) serum IGF-1 concentrations over time in infants in the standard neonatal care and rhIGF-1/rhIGFBP-3 groups (n = 121).

Figure 3.

IGF-1 levels by A, ROP severity* and B, BPD severity^† by postnatal week. *Mean (±SE) serum IGF-1 levels and ROP severity (<3, ≥3) in the rhIGF-1/rhIGFBP-3 and standard neonatal care groups by postnatal week. ^†Mean (±SE) serum IGF-1 levels and BPD severity (mild, moderate, or severe) in the rhIGF-1/rhIGFBP-3 and standard neonatal care groups by postnatal week. Note: If an infant had multiple IGF-1 levels in a day, then IGF-1 level was averaged for the day.

Figure 4.

A, Average weight, B, length, and C, head circumference by treatment group (FAS).