Treatment of Children With GH in the United States and Europe: Long-Term Follow-Up From NordiNet ®  IOS and ANSWER Program

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Abstract

Context

Understanding real-world prescribing of GH may help improve treatment of eligible patients.

Objective

Overall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the United States and Europe.

Design

The American Norditropin Studies: Web-Enabled Research Program (ANSWER; 2002 to 2016, United States) and the NordiNet International Outcome Study (NordiNet IOS; 2006 to 2016, Europe) were multicenter longitudinal observational cohort studies.

Setting

Data were recorded in 207 (United States) and 469 (Europe) clinics.

Participants

Patients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader–Willi syndrome, or born small for gestational age, who commenced GH treatment aged <1 year.

Intervention

GH was prescribed by treating physicians according to local practice.

Main Outcomes Measures

Baseline data and drug doses were recorded. Data on effectiveness and safety were collected.

Results

ANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and one or more GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naive patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the United States vs Europe. No new safety signals of concern were noted.

Conclusions

In most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit–risk profile of GH therapy in children.

Abstract

Two large noninterventional studies (ANSWER and NordiNet IOS) examined real-world use of GH across six indications in children. Prescribing differences were found between the United States and Europe.

Related collections

Most cited references 27

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Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016

Melissa L. Danielson, Rebecca Bitsko, Reem Ghandour … (2018)

The purpose of this study is to estimate the national prevalence of parent-reported attention deficit/hyperactivity disorder (ADHD) diagnosis and treatment among U.S. children 2–17 years of age using the 2016 National Survey of Children’s Health (NSCH). The NSCH is a nationally representative, cross-sectional survey of parents regarding their children’s health that underwent a redesign before the 2016 data collection. It included indicators of lifetime receipt of an ADHD diagnosis by a health care provider, whether the child currently had ADHD, and receipt of medication and behavioral treatment for ADHD. Weighted prevalence estimates were calculated overall and by demographic and clinical subgroups ( n = 45,736). In 2016, an estimated 6.1 million U.S. children 2–17 years of age (9.4%) had ever received an ADHD diagnosis. Of these, 5.4 million currently had ADHD, which was 89.4% of children ever diagnosed with ADHD and 8.4% of all U.S. children 2–17 years of age. Of children with current ADHD, almost two thirds (62.0%) were taking medication and slightly less than half (46.7%) had received behavioral treatment for ADHD in the past year; nearly one fourth (23.0%) had received neither treatment. Similar to estimates from previous surveys, there is a large population of U.S. children and adolescents who have been diagnosed with ADHD by a health care provider. Many, but not all, of these children received treatment that appears to be consistent with professional guidelines, though the survey questions are limited in detail about specific treatment types received. The redesigned NSCH can be used to annually monitor diagnosis and treatment patterns for this highly prevalent and high-impact neurodevelopmental disorder.

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Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society.

Peter Clayton (2000)

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Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study.

M Ranke, A. Lindberg, P Chatelain … (1999)

Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of disease-specific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do not explain all of the variability in growth response, but they have a high degree of precision (low error SDs). Moreover, the parameters used are robust and easily accessible. These properties give the models' practical utility as growth prediction tools. The availability of longitudinal, disease-specific models will be helpful in the future for enabling growth-promoting therapy to be planned at the outset, optimized for efficacy and economy, and individualized to meet treatment goals based on realistic expectations.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Endocrinol Metab

Journal ID (iso-abbrev): J. Clin. Endocrinol. Metab

Journal ID (publisher-id): jcem

Title: The Journal of Clinical Endocrinology and Metabolism

Publisher: Endocrine Society (Washington, DC )

ISSN (Print): 0021-972X

ISSN (Electronic): 1945-7197

Publication date Collection: October 2019

Publication date (Electronic): 15 July 2019

Publication date PMC-release: 15 July 2019

Volume: 104

Issue: 10

Pages: 4730-4742

Affiliations

[1 ] Karolinska Institutet, Karolinska University Hospital , Solna, Sweden

[2 ] Hôpital Necker Enfants Malades , Paris, France

[3 ] Cincinnati Center for Growth Disorders, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine , Cincinnati, Ohio

[4 ] Alder Hey Children’s NHS Foundation Trust , Liverpool, United Kingdom

[5 ] University of Minnesota Masonic Children’s Hospital , Minneapolis, Minnesota

[6 ] University Children’s Hospital, Saarland University Medical Center , Homburg, Germany

[7 ] Novo Nordisk Health Care AG , Zurich, Switzerland

[8 ] Novo Nordisk Inc. , Plainsboro, New Jersey

[9 ] Thomas Jefferson University , Philadelphia, Pennsylvania

[10 ] Nemours/DuPont Hospital for Children , Wilmington, Delaware

Author notes

L.S. and M.P. contributed equally to this study.

Correspondence and Reprint Requests: Lars Sävendahl, MD, PhD, Karolinska University Hospital, J9:30, Visionsgatan 4, 171 64 Solna, Sweden. E-mail: lars.savendahl@ 123456ki.se ; or Michel Polak, MD, PhD, Hôpital Necker Enfants Malades, 149 rue de Sèvres, 75743 Paris, France. E-mail: michel.polak@ 123456aphp.fr .

Author information

Lars Sävendahl http://orcid.org/0000-0003-1067-4976

Article

Publisher ID: 201900775

DOI: 10.1210/jc.2019-00775

PMC ID: 6812718

PubMed ID: 31305924

SO-VID: 0bd68136-a91b-4998-a92b-05fe91f212a4

License:

This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/).

History

Date received : 02 April 2019

Date accepted : 08 July 2019

Page count

Pages: 13

Funding

Funded by: Novo Nordisk 10.13039/501100004191

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Treatment of Children With GH in the United States and Europe: Long-Term Follow-Up From NordiNet ^® IOS and ANSWER Program

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Abstract

Context

Objective

Design

Setting

Participants

Intervention

Main Outcomes Measures

Results

Conclusions

Abstract

Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 27

Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016

Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society.

Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study.

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Cited by 22

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