IGF-1 as a drug for preterm infants: a step-wise clinical development (original) (raw)
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Pediatric Research, 2013
Background: In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP. Methods: In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (Ga) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 µg/kg/24 h. results: Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded. conclusion: In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.
Pediatric Research, 2009
In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 g/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26 -29) and birth weight 1022 g (810 -1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754 -1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59 -1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated. (Pediatr Res 65: 574-579, 2009) Abbreviations: ALS, acid-labile subunit; CL, clearence; FFP, fresh frozen plasma; GHIS, growth hormone insensitivity syndrome; IGFBP-3, insulin like growth factor binding protein 3 0031-3998/09/6505-0574 PEDIATRIC RESEARCH
Iranian journal of pediatrics, 2013
To evaluate early aggressive vs. conservative nutrition and its effect on Retinopathy of Prematurity (ROP) in <32 weeks of gestation neonates. A prospective, randomized, clinical study was conducted in NICU with a total of 75 preterm infants. In the intervention group, infants received early aggressive nutrition immediately after birth, in the control group infants were started on conventional parenteral nutrition (PN). Blood samples were obtained for Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) levels before commencement of PN on the first postnatal day, and from week 1 to 6 every week. All the infants were examined for ROP. Infants in the early aggressive group had a reduction in the risk of ROP of 5% (2 from 40); the number of infants needed treatment averaged 3.7 (2.7 to 5.2). A total of 11 neonates in the conventional group were detected having ROP (P<0.05). Overall, IGF-I levels were higher in the aggressive PN (APN) vs t...
rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial
The Journal of Pediatrics
and on behalf of the study team* 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.
American Journal of Perinatology, 2019
Objective To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1–binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. Study Design Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. Results Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompani...
Insulin-like growth factor 1 has multisystem effects on fetal and preterm infant development
Acta paediatrica (Oslo, Norway : 1992), 2016
Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin-like growth factor 1 (IGF-1) axis is the major hormonal mediator of growth in utero and levels of IGF-1 are often very low after preterm birth. We reviewed the role of IGF-1 in fetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF-1 deficiency in preterm morbidities. There is a rationale for clinical trials to evaluate the potential benefits of IGF-1 replacement in very preterm infants. This article is protected by copyright. All rights reserved.
Early Human Development, 1996
Cord sera were obtained from term, Chilean newborns exhibiting various patterns of intrauterine growth and assayed for IGF-I, IGF-2, IGFBP-I, IGPBP-2, and IGFESP-3 by specific radioimmunoassays @IA). Serum levels of each peptide were correlated with birth weight (BW), ponderal index (PI), and placental weight (PW). Total IGF-I levels correlated with BW (r = 0.665, P = O.OOOl), PI (r = 0.527, P = 0.004), and PW (r = 0.596, P = 0.0017). Iu contrast, IGF-2 failed to correlate with any growth parameter. Of the three binding proteins, IGFEP-3 exhibited the strongest relationship to each growth parameter. IGPIW-3 correlated significantly with BW (r = 0.71, P i O.OOOl), PI (r = 0.782, P < O.OOOl), and PW (r = 0.57, P = 0.0029). In addition IGFFSP-3 levels positively correlated to IGF-1 levels (r = 0.614, P = 0.0005). By contrast, circulating IGFBP-1 and IGFBP-2 were inversely related to IGF-I levels. A11 five peptides were subjected to multiple regression analysis and *Corresponding author. Tel.: + 1 314 4542114; fax: + 1 314 7217480 0378-3782/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PIf SO378-3782(96)01737-9 16 M. Osorio et al. I Early Hutnan Development 46 (1996) 15-26