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Submitted on January 29, 2007
Accepted on March 1, 2007
Department of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, Los Angeles, CA, United States, 90095; Department of Pediatrics, University of Virginia, Charlottesville, VA, United States, 22908; Medical Department, Novo Nordisk Inc., Princeton, NJ, United States, 08540; Scientific Marketing GHT, Novo Nordisk A/S, Virum, Denmark, DK 2830; Medical Affairs, Lucile Packard Foundation for Children's Health, Palo Alto, CA, United States, 94304
* To whom correspondence should be addressed. E-mail: hassy{at}mednet.ucla.edu.
Context: Weight-based dosing of GH is the standard-of-care for short-children, although IGF-I is thought to be the main mediator of GH-actions on growth.
Objective: To test whether IGF-I levels achieved during GH therapy are determinants of the growth-responses to GH-treatment.
Design: Two-year, open-label, randomized, IGF-I concentration-controlled-trial. Prepubertal short-children (n=172, mean age=7.53 yrs, mean height-SDS [HT-SDS]=-2.64) with low IGF-I levels (mean IGF-I SDS=-3.56) were randomized to receive one of two GH dose-titration arms in which GH-dosage was titrated to achieve an IGF-I SDS at the mean (IGF(low) group, n=70), or the upper-limit of the normal-range (+2 SDS, IGF(high) group, n=68) or to a comparison-group of conventional-GH-dose of 40 µg/kg/d (n=34).
Setting: Multi-center, outpatient.
Primary-Outcome-Measure: Change in HT-SDS over 2-years.
Results: 147 patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1 and +1.6 for conventional, IGF(low), and IGF(high), respectively, with IGF(high) showing significantly greater linear-growth response (P<0.001 compared to the other two groups). The IGF(high) arm required higher doses (>2.5 times) than the IGF(low) arm and these GH doses were highly variable (20-346 mcg/kg/day). Multivariate-analyses suggested that the rise in the IGF-I SDS significantly impacted height-outcome along with the GH-dose and the pretreatment peak stimulated-GH level.
Conclusion: IGF-I-based GH-dosing is clinically-feasible and allows maintaining serum-IGF-I concentrations within the desired target-range. Titrating the GH-dose to achieve higher IGF-I targets results in improved growth-responses, although at higher average GH doses.
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