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.