Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity.

CONTEXT: Children with severe IGF-I deficiency due to congenital or acquired defects in GH action have short stature that cannot be remedied by GH treatment. OBJECTIVES: The objective of the study was to examine the long-term efficacy and safety of recombinant human IGF-I (rhIGF-I) therapy for short children with severe IGF-I deficiency. DESIGN: Seventy-six children with IGF-I deficiency due to GH insensitivity were treated with rhIGF-I for up to 12 yr under a predominantly open-label design. SETTING: The study was conducted at general clinical research centers and with collaborating endocrinologists. SUBJECTS: Entry criteria included: age older than 2 yr, sd scores for height and circulating IGF-I concentration less than -2 for age and sex, and evidence of resistance to GH. INTERVENTION: rhIGF-I was administered sc in doses between 60 and 120 microg/kg twice daily. MAIN OUTCOME MEASURES: Height velocity, skeletal maturation, and adverse events were measured. RESULTS: Height velocity increased from 2.8 cm/yr on average at baseline to 8.0 cm/yr during the first year of treatment (P < 0.0001) and was dependent on the dose administered. Height velocities were lower during subsequent years but remained above baseline for up to 8 yr. The most common adverse event was hypoglycemia, which was observed both before and during therapy. It was reported by 49% of treated subjects. The next most common adverse events were injection site lipohypertrophy (32%) and tonsillar/adenoidal hypertrophy (22%). CONCLUSIONS: Treatment with rhIGF-I stimulates linear growth in children with severe IGF-I deficiency due to GH insensitivity. Adverse events are common but are rarely of sufficient severity to interrupt or modify treatment.

Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature.

CONTEXT: Small clinical trials of GH treatment of idiopathic short stature (ISS) show variable efficacy. OBJECTIVE: The study was an analysis of a large GH registry for efficacy and safety of GH treatment of ISS. There was also a comparison with a specific clinical trial. DESIGN: Up to 7 yr of GH treatment of ISS was evaluated for efficacy and safety in the National Cooperative Growth Study (NCGS). SETTING: The NCGS study was conducted at Genentech, Inc. and included 47,226 patients. PATIENTS: The ISS group included maximum stimulated GH 10 ng/ml or more and/or a report of ISS by investigator (n = 8018; all included for safety). Cohort 1 (n = 2520) was similar to the clinical trial, cohort 2 (n = 283) included subjects younger than 5 yr of age, and cohort 3 (n = 940) was pubertal at GH start. INTERVENTION: GH, approximately 0.30 mg/kg.wk, was given. MAIN OUTCOME MEASURES: These included growth velocities and height sd (HtSDS). RESULTS: Mean first-year growth velocities in cohorts 1, 2, and 3 increased 4.6, 3.9, and 4.4 cm/yr over pretreatment, respectively. Measures included: baseline mean HtSDS, -2.9, -3.2, and -2.8; mean HtSDS at 1 yr, -2.4, -2.3, and -2.3, respectively. Mean HtSDS after 7 yr in cohorts 1 (n = 303) and 2 (n = 85) and 5 yr in cohort 3 (n = 58) were: -1.2, -1.0, and -1.5, respectively. Cohort 3 shorter treatment time was due to advanced baseline age (mean 13.8 yr) and puberty. Mean HtSDS gain in cohort 1 was comparable with the clinical trial. No new safety signals specific to the NCGS ISS population were observed. CONCLUSION: ISS patients in the GH registry demonstrate a significant increase in HtSDS with the safety profile similar to GH-deficient patients. RESULTS were similar to the clinical trial.

Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial.

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.

Managing the child with severe primary insulin-like growth factor-1 deficiency (IGFD): IGFD diagnosis and management.

Growth failure associated with severe primary insulin-like growth factor 1 (IGF-1) deficiency (SPIGFD), a condition defined as basal IGF-1 standard deviation score (SDS) less than or equal to -3 and height SDS less than or equal to -3 in a child with normal or elevated levels of growth hormone, can be successfully treated with the recombinant human IGF-1 mecasermin. In this review, we describe the most safe and effective way to use mecasermin in the treatment of patients with SPIGFD, including how to initiate dosing, key side effects, and how to monitor treatment. Finally, mention of how to reinitiate therapy is made, given the recent drug shortage with mecasermin.

Adult and near-adult height in patients with severe insulin-like growth factor-I deficiency after long-term therapy with recombinant human insulin-like growth factor-I.

BACKGROUND: Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). AIMS: To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. METHODS: Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. RESULTS: Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. CONCLUSION: Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range.