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

      , MD, PhD 1 , , MD, PhD 2 , , MD, PhD 1 , , MD 3 , , MD, PhD 4 , , DM, FMedSci 5 , , MD 6 , , MD 7 , , MD 6 , , MD 8 , , MRCPCH 9 , , MD, OD 10 , , MB.BS, PhD 11 , , MD, PhD 12 , , MD, PhD 13 , , MD, PhD 14 , , MD, PhD 15 , , MS 14 , , MBA 14 , , MD, MPH 15 , , PhD 14 , , MRCPCH, PhD 16 , , MD, PhD 17 , , MD, PhD 18 , on behalf of the study team

      The Journal of pediatrics

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          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.

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          Most cited references 44

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          Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial.

          To determine whether earlier treatment using ablation of the avascular retina in high-risk prethreshold retinopathy of prematurity (ROP) results in improved grating visual acuity and retinal structural outcomes compared with conventional treatment. Infants with bilateral high-risk prethreshold ROP (n = 317) had one eye randomized to early treatment with the fellow eye managed conventionally (control eye). In asymmetric cases (n = 84), the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management. High risk was determined using a model based on the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity natural history cohort. At a corrected age of 9 months, visual acuity was assessed by masked testers using the Teller acuity card procedure. At corrected ages of 6 and 9 months, eyes were examined for structural outcome. Outcomes for the 2 treatment groups of eyes were compared using chi2 analysis, combining data for bilateral and asymmetric cases. Grating acuity results showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.5% to 14.5% (P =.01). Unfavorable structural outcomes were reduced from 15.6% to 9.1% (P<.001) at 9 months. Further analysis supported retinal ablative therapy for eyes with type 1 ROP, defined as zone I, any stage ROP with plus disease (a degree of dilation and tortuosity of the posterior retinal blood vessels meeting or exceeding that of a standard photograph); zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease. The analysis supported a wait-and-watch approach to type 2 ROP, defined as zone I, stage 1 or 2 ROP without plus disease or zone II, stage 3 ROP without plus disease. These eyes should be considered for treatment only if they progress to type 1 or threshold ROP. Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree. Additional analyses led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP. Long-term follow-up is being conducted to learn whether the benefits noted in the first year after birth will persist into childhood.
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            Target ranges of oxygen saturation in extremely preterm infants.

            Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.) 2010 Massachusetts Medical Society
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              Oxygen saturation and outcomes in preterm infants.

              The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).
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                Author and article information

                Journal
                0375410
                5127
                J Pediatr
                J. Pediatr.
                The Journal of pediatrics
                0022-3476
                1097-6833
                11 January 2019
                22 November 2018
                March 2019
                01 March 2019
                : 206
                : 56-65.e8
                Affiliations
                [1 ]Skane University Hospital, Department of Clinical Sciences Lund, Pediatrics, Lund University, Lund, Sweden;
                [2 ]Department of Neonatology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden;
                [3 ]Careggi University Hospital of Florence, University of Florence, Florence, Italy;
                [4 ]Genova Neonatal Intensive Care Unit, Istituto Giannina Gaslini, Genova, Italy;
                [5 ]Department of Academic Neonatology, UCL EGA Institute for Women’s Health, UCL, London, United Kingdom;
                [6 ]Department of Pediatrics and the Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom;
                [7 ]Neonatal Perinatal Medicine, Department of Pediatrics, The Children’s Hospital at the University of Oklahoma Health Sciences Center, Oklahoma City, OK;
                [8 ]Department of Pediatrics, Brody School of Medicine, East Carolina University, Greenville, NC;
                [9 ]St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre and Division of Developmental Biology and Medicine, School of Medical Sciences, University of Manchester, Manchester, United Kingdom;
                [10 ]The Department of Pediatrics and Ophthalmology, University of Wisconsin, Madison, WI;
                [11 ]Neonatal Intensive Care Unit, St Peter’s Hospital, Chertsey, Surrey, United Kingdom;
                [12 ]Department of Woman and Child Health, University Hospital A. Gemelli, IRCCS, Rome, Italy;
                [13 ]Department of Pediatrics, Division of Neonatology, VU University Medical Center, Amsterdam, The Netherlands;
                [14 ]Global Clinical Development, Rare Metabolic Diseases, Shire, Lexington, MA;
                [15 ]Global Clinical Development, Rare Metabolic Diseases, Shire, Zug, Switzerland;
                [16 ]Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom;
                [17 ]Harvard Medical School, Boston Children’s Hospital, Boston, MA;
                [18 ]Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden
                Author notes
                [*]

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

                Reprint requests: David Ley, MD, PhD, Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Pediatrics, Lund 211 85, Sweden. david.ley@ 123456med.lu.se
                Article
                NIHMS1004391
                10.1016/j.jpeds.2018.10.033
                6389415
                30471715

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Pediatrics

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