Context: Short stature in children may be associated with low IGF-I despite normal stimulated GH levels and without other causes.

Objective: Our objective was to assess the safety and efficacy of recombinant human IGF-I (rhIGF-I) in short children with low IGF-I levels.

Design: This was a 1-yr, randomized, open-label trial (MS301).

Setting: The study was conducted at 30 U.S. pediatric endocrinology clinics.

Subjects: A total of 136 short, prepubertal subjects with low IGF-I (height and IGF-I SD scores <-2, stimulated GH 7 ng/ml); 124 completed the study, and six withdrew for adverse events and six for other reasons.

Intervention: rhIGF-I was administered sc, twice daily using weight-based dosing (40, 80, or 120 μg/kg; n = 111) or subjects were observed (n = 25).

Main Outcome Measures: First-year height velocity (centimeters per year, cm/yr), height SD score, IGF-I, and adverse events were prespecified outcomes.

Results: First-year height velocities for subjects completing the trial were increased for the 80- and 120-μg/kg twice-daily vs. the untreated group (7.0 ± 1.0, 7.9 ± 1.4, and 5.2 ± 1.0 cm/yr, respectively; all P < 0.0001) and for the 120- vs. 80-μg/kg group (P = 0.0002) and were inversely related to age. They were not predicted by GH stimulation or IGF-I generation test results and were not correlated with IGF-I antibody status. The most commonly reported adverse events of special interest during treatment were headache (38% of subjects), vomiting (25%), and hypoglycemia (14%).

Conclusions: rhIGF-I treatment was associated with age- and dose-dependent increases in first-year height velocity. Adverse events during treatment were less common than in previous studies and were generally transient, easily managed, and without known sequelae.