ESPEYB16 4. Growth and Growth Factors Clinical Trials (1 abstracts)
4.6. rhIGF-1/rhIGFBP-3 in preterm Infants: A phase 2 randomized controlled trial
Ley D , Hallberg B , Hansen-Pupp I , Dani C , Ramenghi LA , Marlow N , Beardsall K , Bhatti F , Dunger D , Higginson JD , Mahaveer A , Mezu-Ndubuisi OJ , Reynolds P , Giannantonio C , van Weissenbruch M , Barton N , Tocoian A , Hamdani M , Jochim E , Mangili A , Chung JK , Turner MA , Smith LEH & Hellström A
Skane University Hospital, Department of Clinical Sciences Lund, Pediatrics, Lund University, Lund, Sweden, david.ley@med.lu.se.
To read the full abstract: J Pediatr. 2019;206:56–65.e8.
IGF-I plays a key role in fetal growth and development [1]. IGF-I exerts pleiotropic effects including cell proliferation, survival and differentiation, but also influencing metabolism and angiogenesis.
Very preterm newborns show a rapid decline serum IGF-I concentrations that remain low for the first weeks of life relative to corresponding fetal levels in utero. Lower IGF-I levels in extremely preterm infants have been associated with an increased risk of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), neurodevelopmental delay and growth impairment [2]. In animal models, IGF-I administration reduces the risk of developing oxygen-induced retinopathy [3] and has protective effects on lung and brain damage. A complex of recombinant human Insulin-like Growth Factor-I and recombinant human Insulin-like Growth Factor Binding Protein-3 (rhIGF-I/rhGFBP-3) was developed to increase the half-life of rhIGF-I and reduce the incidence of side effects, mainly hypoglycemia, associated with the use of rhIGF-I alone. In a previous trial conducted by the same Swedish team, the infusion of rhIGF-I/rhIGFBP-3 in preterm infants increased circulating levels of IGF-I without major safety concerns [4].
This phase II, randomized, multicenter trial tested the efficacy and safety of rhIGF-I/rhGFBP-3 infusion in extremely premature infants. The primary efficacy outcome measure was the incidence of ROP, the secondary efficacy outcomes were the incidence of other morbidities and the discharge time. 121 infants born from 23 to 27 weeks gestational age were enrolled and randomized to standard care (n=60) or to continuous intravenous infusion of rhIGF-I/rhGFBP-3 (250 mcg/kg per 24 hours, from <24 hours of birth to postmenstrual age 29 weeks) (n=61) with the intention of maintaining serum IGF-I levels within 28–109 mcg/l. Target exposure (based on IGF-I levels and overall infusion duration) was achieved in only 24/61 treated subjects. ROP severity and incidence as well as discharge time and growth were unaffected by rhIGF-I/rhGFBP-3. The incidence and severity of bronchopulmonary dysplasia (BPD) were significantly reduced in infants treated with rhIGF-I/rhGFBP-3, and a tendency to milder forms of intraventricular hemorrhage was also observed. The rhIGF-I/rhGFBP-3 complex was well tolerated. Fatal SAEs were reported in 19.7% of treated infants compared with 11.7% of controls, although none was considered related to therapy.
Overall, although the results of this trial are inconclusive, the potential beneficial effect on BPD deserves further studies in larger cohorts of extremely preterm infants. However, it has to be pointed out that all intervention studies in this type of population are inevitably and heavily affected by a number of confounders such as late pregnancy events, modes of delivery, transfusions, infections, antibiotic/probiotic use, nutrition and comorbidities as well as the standard care provided in different neonatology units.
References: 1. Hwa V, Fang P, Derr MA, Fiegerlova E, Rosenfeld RG. IGF-I in human growth: lessons from defects in the GH-IGF-I axis. Nestle Nutr Inst Workshop Ser 2013;71:43–55.
2. Hellstrom A, Engstrom E, Hard AL, Albertsson-Wikland K, Carlsson B, Niklasson A, Lofqvist C, Svensson E, Holm S, Ewald U, Holmstrom G, Smith LE. Postnatal serum insulin-like growth factor I deficiency is associated with retinopathy of prematurity and other complications of premature birth. Pediatrics 2003;112:1016–1020.
3. Vanhaesebrouck S, Daniels H, Moons L, Vanhole C, Carmeliet P, De Zegher F. Oxygen-induced retinopathy in mice: amplification by neonatal IGF-I deficit and attenuation by IGF-I administration. Pediatr Res 2009;65:307–310.
4. Hansen-Pupp I, Hellstrom A, Hamdani M, Tocoian A, Kreher NC, Ley D, Hallberg B. Continuous longitudinal infusion of rhIGF-1/rhIGFBP-3 in extremely preterm infants: Evaluation of feasibility in a phase II study. Growth Horm IGF Res 2017;36:44–51.
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