Attaining genetic height potential: Analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years

https://doi.org/10.1016/j.ghir.2015.08.006Get rights and content

Highlights

  • We evaluated the effects of 5 years of growth hormone (GH) treatment on height standard deviation scores (HSDS).

  • Patients were previously GH-untreated children with short stature.

  • Each diagnostic group experienced significant increases in mean HSDS, which approached their genetic height potential.

  • Height velocity at 4 months after start of treatment was the most significant and strongest predictor of ΔHSDS.

Abstract

Objective

This study aimed to assess attainment of genetic height potential after long-term growth hormone (GH) treatment in GH-naïve children diagnosed with isolated growth hormone deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), born small for gestational age (SGA), or idiopathic short stature (ISS) enrolled in the American Norditropin® Studies: Web-enabled Research (ANSWER) Program.

Design

Children with IGHD (n = 2884), MPHD (n = 200), SGA (n = 481), or ISS (n = 733) with baseline height standard deviation score (HSDS) ≤− 2 were assessed over 5 years of GH treatment for mean HSDS, change in HSDS (ΔHSDS), and corrected HSDS (HSDS  target HSDS).

Results

Mean HSDS and corrected HSDS significantly increased to close to target height across all diagnostic groups after 5 years of GH treatment (P < 0.0001). ∆HSDS at year 5 increased for all groups (IGHD: 1.8; MPHD: 2.1; SGA: 1.8; ISS: 1.6). Among patients who continued GH for 5 years, mean insulin-like growth factor-I (IGF-I) SDS increased to within normal range across all groups. Body mass index (BMI) SDS remained relatively stable in all diagnostic groups. Bone age (BA) increased, and the mean BA to chronological age (BA/CA) ratio reached or approached 1 across diagnostic groups over 5 years of GH treatment.

Conclusions

Long-term GH therapy resulted in a significant increase in mean HSDS and corrected HSDS from baseline values in all diagnostic groups. The observed increase in mean corrected HSDS is consistent with growth that approached the patients' genetic height potential, although complete height gains will be evaluated at the attainment of final height.

Introduction

Recombinant human growth hormone (GH) is an effective growth-promoting therapy for children with short stature or growth failure due to a number of conditions causing either a deficiency of, or lack of responsiveness to, endogenous growth hormone. The US Food and Drug Administration has approved the use of GH replacement therapy for the treatment of children with growth hormone deficiency (GHD), which includes patients with isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD); children born small for gestational age (SGA); children with short stature or growth failure associated with Turner syndrome (TS) or Noonan syndrome (NS); and children with idiopathic short stature (ISS), Prader–Willi syndrome, chronic kidney disease (CKD), or short stature homeobox (SHOX) gene haploinsufficiency [1].

Recombinant GH treatment improves short-term linear growth and adult height achieved in children with various disorders associated with short stature or growth failure; however, clinical studies have shown that treatment outcomes can be highly variable [1], [2], [3], [4]. Attainment of target height is an important treatment goal for GH therapy in children with growth disorders because of the positive benefits it has on health-related quality of life and on physical and psychosocial well-being [5], [6], [7], [8]. Analyses of large data sets from pediatric patient registries have consistently demonstrated that early initiation and longer duration of prepubertal GH treatment are significantly correlated with greater gains in height standard deviation score (HSDS) and achievement of HSDS consistent with the genetic height potential for children with IGHD, MPHD, and other causes of growth failure or short stature [3], [9], [10], [11], [12], [13], [14], [15], [16].

Norditropin® [somatropin (recombinant DNA origin) injection, Novo Nordisk A/S, Bagsvaerd, Denmark], hereafter referred to as GH, has been approved for the treatment of children with growth failure due to growth hormone deficiency (IGHD or MPHD) or with short stature associated with NS, TS, or SGA with no catch-up growth by 2 to 4 years of age; it has also been approved for the treatment of adults with adult- or childhood-onset GHD [17]. The American Norditropin Studies: Web-enabled Research (ANSWER) Program is a noninterventional, observational study to evaluate the long-term effectiveness and safety of Norditropin® in patients with growth disorders [18]. The ANSWER Program (utilizing NovoNet®, the Novo Nordisk Web-based research platform) also evaluates factors predictive of patient response to GH treatment. Data from the ANSWER Program have shown that children with IGHD, MPHD, ISS, TS, NS, or SGA exhibit increases from baseline height in HSDS (ΔHSDS) following 2 years of GH treatment [18], [19], [20]. Similar results have been reported in other registries, including the National Cooperative Growth Study (NCGS), the Pfizer International Growth Study (formerly Kabi International Growth Study [KIGS]), and the NordiNet® International Outcome Study (IOS) [21], [22]. Factors identified as positively correlated with ΔHSDS over 2 years of GH treatment in patients with GHD were height velocity (HV) after 4 months of treatment and pre-treatment body mass index (BMI) SDS. In contrast, age, HSDS, and serum insulin-like growth factor-I (IGF-I) SDS at baseline were negatively correlated with ΔHSDS, while no consistent effect of gender was observed [19], [23]. However, in the joint analysis of the IOS and ANSWER Program studies, gender was shown to have an effect on growth in prepubertal patients with GHD or SGA (significantly greater ∆HSDS was reported in boys compared with girls) [24].

The principal aim of the current analysis of data from the ANSWER Program was to evaluate the long-term effects of GH treatment in achieving genetic height potential in previously untreated pediatric patients with IGHD, MPHD, SGA, or ISS. Height outcomes were determined by auxologic assessment and by calculation of HSDS and corrected HSDS from baseline through year 5 of GH treatment. The expectation is that patients from all diagnostic groups will have shown improvement in HSDS and have attained corrected HSDS consistent with their genetic height potential.

Section snippets

Study design

The ANSWER Program is an ongoing observational study initiated in 2002 that has collected long-term effectiveness and safety information on more than 13,000 pediatric patients treated with Norditropin® [18]. Physicians participating in the ANSWER Program provide updated patient histories and physical examination data utilizing NovoNet®. Patients were enrolled in the study at the discretion of the participating physician investigators. Patients or their parents or guardians provided informed

Patient demographics and characteristics at baseline

A total of 4297 children who were GH-naïve with IGHD ( N= 2884), MPHD ( N= 200), SGA ( N= 481), and ISS ( N= 732) were included in the analysis. Demographics and baseline characteristics for each diagnostic patient cohort are presented in Table 1.

At baseline (Table 1), the lowest mean peak serum GH concentration (ng/mL) in response to stimulation was observed in patients with IGHD (6.0 ± 2.6, n = 2106) or MPHD (4.1 ± 3.8, n = 96) compared with patients with SGA (14.9 ± 10.0, n = 146) and ISS (17.6 ± 9.8, n = 486).

Discussion

Results of the current analyses have shown that continued GH treatment for up to 5 years provided positive effects on height and other measures of auxologic assessment in children who were GH-naïve with IGHD, MPHD, SGA, and ISS. Long-term GH therapy resulted in significant increases in mean HSDS and corrected HSDS from baseline to year 5. In addition, the increase in corrected HSDS indicated that the growth response to long-term (5 year) GH treatment approached the genetic height potential for

Conclusions

In conclusion, long-term GH therapy over 5 years was associated with increases in mean HSDS in previously untreated pediatric patients with IGHD, MPHD, ISS, or SGA. Additionally, GH treatment was associated with HSDS approaching genetic height potential based on patient target heights, with a statistically significant increase over time in corrected HSDS observed in patients across all diagnostic groups. Total height gains, however, will need to be evaluated at the attainment of final height.

Conflicts of interests

Judith L. Ross, MD is a consultant for Novo Nordisk and Eli Lilly and receives research support from Novo Nordisk and Eli Lilly.

Peter A. Lee, MD, PhD is a consultant for Novo Nordisk, Abbvie, and Ipsen and receives research support from Pfizer, Novo Nordisk, Eli Lilly, Tercica, and Abbvie.

Robert Gut, MD, PhD is an employee of Novo Nordisk, Inc., Princeton, NJ, USA.

John Germak, MD is an employee of Novo Nordisk, Inc., Princeton, NJ, USA.

Acknowledgments

Editorial and writing assistance were provided by Jeffrey M. Palmer, PhD, ETHOS Health Communications, Newtown, Pennsylvania, with financial assistance from Novo Nordisk Inc., Princeton, New Jersey, in compliance with international guidelines on Good Publication Practice. The ANSWER Program was sponsored by Novo Nordisk Inc., Plainsboro, New Jersey.

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