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PP-42 Evaluation of rhigf-1/rhigfbp-3 to establish and maintain physiological intrauterine serum igf-1 levels early after birth in extremely preterm infants
  1. Turner1,
  2. Hallberg2,
  3. Ingrid3,
  4. Hellström4,
  5. Ley3,
  6. Mangili5,
  7. Tocoian5,
  8. Barton5,
  9. Chung5
  1. 1University of Liverpool, LIVERPOOL, UK
  2. 2Department of Neonatology, CLINTEC, Karolinska Institutet/University Hospital, STOCKHOLM, Sweden
  3. 3Lund University, Skåne University Hospital, Institute of Clinical Sciences Lund, LUND, Sweden
  4. 4Institute of Neuroscience and Physiology, Sahlgrenska Academy, GOTHENBURG, Sweden
  5. 5Shire, LEXINGTON, MA, USA

Abstract

Background We conducted a phase 2 trial evaluating IGF-1 supplementation with recombinant human (rh)IGF-1/rhIGFBP-3 for prevention of complications of prematu-rity in extremely preterm infants. The primary endpoint of reduction in severity of retinopathy of prematurity (ROP) was not met; however, improvements were seen in im-portant secondary endpoints, including bronchopulmo-nary dysplasia (BPD) and intraventricular haemorrhage (IVH). In order to understand the potential influence of the rhIGF-1/rhIGFBP-3 dose regimen on outcomes, and the overall appropriateness of dosing, we evaluated se-rum IGF-1 levels, target range attainment, and correlation of IGF-1 levels with outcomes, during the trial.

Methods Infants born at gestational age (GA; wk+d) 23+0 to 27+6 were randomised to rhIGF-1/rhIGFBP-3 or standard care. rhIGF-1/rhIGFBP-3 was administered at a dose of 250 µg/kg/24 hour (selected based on prior phar-macokinetic modelling) via continuous intravenous (IV) infusion from birth up to a postmenstrual age of 29 wk +6 d. Target levels for serum IGF-1 were 28’ ’109 µg/L (normal physiological intrauterine levels for GA 23–28 wk based on published literature). Target drug exposure was ≥70% IGF-1 values within target range and ≥70% intended du-ration of therapy. Serum IGF-1 levels were measured us-ing a validated radioimmunoassay at a central laboratory.

Results 121 infants were enrolled; 61 (63.9% male) were randomised to rhIGF-1/rhIGFBP-3, 60 (65.0% male) to standard care. 35/61 treated infants (57.4%), and 32/60 in-fants (53.3%) in the standard care group, were born at GA<26 wk. Mean (range) average daily dose of rhIGF-1/rhIG-FBP-3 was 248.1 (131.1–250.0) µg/kg/24 hour for the treated group. Mean (range) duration of exposure was 23.8 (0.1–45.3) days. Among treated infants, 56/61 received ≥70% intended duration of treatment and 28/61 had ≥70% of IGF-1 levels within target range. Overall target expo-sure was achieved for 24/61 treated infants. For rhIGF-1/rhIGFBP-3 treated infants, 66.2% of IGF-1 measurements were within target range vs 6.3% for the standard neo-natal care group. Mean serum IGF-1 was within target range for the rhIGF-1/rhIGFBP-3 group (39.6 µg/L) during treatment and below target for the C group (17.6 µg/L) over the same period. Very few IGF-1 measurements (1.5%) in treated infants were above the upper bound of the targeted range. Onset of endogenous IGF-1 produc-tion was estimated at around week 32 (corresponding approximately with cessation of treatment), after which both groups had IGF-1 levels within target range. In treat-ed infants, trends were observed towards lower severity of ROP (despite lack of improvement overall) and lower severity of BPD with higher serum IGF-1. Numbers of IVH events were too small to evaluate correlation with IGF-1.

Conclusion Treatment with rhIGF-1/rhIGFBP-3 at 250 µg/kg/24 hour (continuous IV infusion) achieved serum IGF-1 levels within the targeted physiological intrauterine range for ~two-thirds of measurements in treated infants. Mean IGF-1 levels were within target for treated infants but were close to the lower bound of the target range. We anticipate target level attainment could be further opti-mised to potentially improve outcomes. A phase 2b/3 tri-al is planned to continue evaluation of rhIGF-1/rhIGFBP-3 for prevention of complications of prematurity, and will explore a second, higher dose.

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