Elsevier

The Journal of Pediatrics

Volume 206, March 2019, Pages 56-65.e8
The Journal of Pediatrics

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

https://doi.org/10.1016/j.jpeds.2018.10.033Get rights and content
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open access

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 230/7 weeks to 276/7 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 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 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

neonatology
retinopathy of prematurity
bronchopulmonary dysplasia
intraventricular hemorrhage

Abbreviations

AE
Adverse event
BPD
Bronchopulmonary dysplasia
ES
Evaluable set
FAS
Full analysis set
IGF-1
Insulin-like growth factor-1
IVH
Intraventricular hemorrhage
NEC
Necrotizing enterocolitis
PMA
Postmenstrual age
rh
Recombinant human
ROP
Retinopathy of prematurity
rhIGF-1/rhIGFBP-3
rhIGF-1 complexed with its binding protein rhIGFBP-3
SAE
Serious AE

Cited by (0)

Detailed affiliations available at www.jpeds.com

Funded by Shire. Shire participated in the design of the study, the collection and analysis of data, and preparation of the clinical study report. D.L. and I.H-P. hold stock/stock options in Premalux AB, and received consulting fees from Shire. B.H. received consulting fees from Premacure AB and Shire. L.R. received consulting fees and research support from Shire. N.M. received consulting fees from Shire, and partial funding from the Department of Health's National Institute for Health Research Biomedical Research Centre's funding scheme at University College London Hospitals/University College London. K.B., F.B., J.H., O.M-N., M.vW., and L.S. received consulting fees from Shire. D.D. received consulting fees from Shire, and received consulting fees from Ipsen regarding other indications for IGF-1 therapies. N.B., A.T., M.H., E.J., A.M., and J-K.C. are employees of and own stock/stock options in Shire. M.T.'s university received consulting fees from Shire. A.H. holds stock/stock options in Premalux AB, and received consulting fees from Shire. C.D., A.M., P.R, and C.G. declare no conflicts of interest.

*

List of additional members of the study team is available at www.jpeds.com (Appendix 1).