Study of Growth-promoting and Metabolic Effects of Growth Hormone (rhGH)

Study Overview
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Brief Summary
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Recombinant growth hormone (rhGH) treatment is widely used in France to normalize height during childhood and final height in children born small for gestational age (SGA). Because rhGH has been associated with increased insulin levels and insulin resistance, concern has been expressed regarding the late consequences of rhGH treatment on risk factors for diabetes mellitus type II and metabolic syndrome, especially in possibly predisposed subjects as SGA children.

Detailed Description
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Recombinant growth hormone (rhGH) treatment is widely used in France to normalize height during childhood and final height in children born small for gestational age (SGA). Because rhGH has been associated with increased insulin levels and insulin resistance, concern has been expressed regarding the late consequences of rhGH treatment on risk factors for diabetes mellitus type II and metabolic syndrome, especially in possibly predisposed subjects as SGA children. Because rhGH use in this population will sharply increase in the coming years, our purpose is to identify and analyze factors that predispose these children born SGA to the metabolic consequences of rhGH therapy. The main objective of this study is to identify and analyze factors implicated in the variability of the metabolic and growth responses to rhGH treatment in children born SGA. We want to: Quantify the metabolic effects of rhGH treatment by analyzing insulin levels, insulin sensitivity and lipid profile (lipolysis and ketogenesis); Evaluate the effects of two different rhGH regimens on the growth of children born SGA; Determine if the metabolic effects of rhGH therapy correlate to the growth responses in the two groups; Identify factors, especially genetic factors, responsible for the variations in individual metabolic and growth-promoting effects of rhGH in children born SGA. This is a randomized, open-labeled, 2-year study, which will compare two regimens of rhGH therapy on the growth responses and metabolic effects in short children born SGA. 100 prepubertal, non GH deficient, short children (height < -3 SDS) born SGA (birth height < -2 SDS) will be randomized to receive either the recommended dose in the EU of rhGH (Norditropine SimpleXx®), or the dose to achieve a treat-to target value of IGF-1 levels within a +1.5 to +2.5 SDS interval (starting dose, 0.067 mg/kg/day) for 24 months. Metabolic effects of rhGH treatment will be evaluated by body mass index (BMI), fasting insulin and glucose levels, HOMA index of insulin resistance, insulin and glucose levels during OGTT, HbA1C and fasting serum lipids (free fatty acids, 3-hydroxybutyrate, total cholesterol, LDL and HDL cholesterol, triglycerides). Height, growth velocity, IGF-1 and IGF-BP3 levels will evaluate growth response of rhGH treatment. Polymorphisms of different genes of the signaling pathway of GH and insulin will be analyzed in order to search for those possibly responsible for the variability in metabolic and growth responses during rhGH treatment in SGA children.

Official Title
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Study of Growth-promoting and Metabolic Effects of Growth Hormone (rhGH) by Comparison of Two Regimens of rhGH Administration to SGA Children. Pharmacogenetics of Metabolic Responses to rhGH

Conditions
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Small for Gestational Age

Intervention / Treatment
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* Drug: rhGH (Norditropine SimpleXx®)
* Drug: rhGH norditropine simple Xx


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prepubertal age Prepubertal characteristics Non GH deficient Short children (height < -2.5 SDS) Born SGA (birth height < -2 SDS) Parental height adjusted (< -1 DS) No rhGH treatment before inclusion Exclusion Criteria: ALLERY to rhGH or excipients Small height etiologies Cancer or cancer treatment ongoing Drugs interference with growth Mental impairment Hypertrophic cardiopathy impairment Hypertension not under controlled Intra cranial hypertension not controlled Diabetes and hyperglycaemia without diabetes Dyslipidemia Hepatitis Kidney failure Chromosomic aberration and/or genetic disorders (except Silver Russel Syndrome) No social security State of health in worst conditions after cardiac surgery, polytraumatism

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>the recommended dose in the EU of rhGH (Norditropine SimpleXx®) | Drug: rhGH (Norditropine SimpleXx®)<br>* the recommended dose in the EU of rhGH (Norditropine SimpleXx®<br>|
| Active Comparator: 2<br>the dose to achieve a treat-to target value of IGF-1 levels within a +1.5 to +2.5 SDS interval (starting dose, 0.067 mg/kg/day) | Drug: rhGH norditropine simple Xx<br>* the dose to achieve a treat-to target value of IGF-1 levels within a +1.5 to +2.5 SDS interval (starting dose, 0.067 mg/kg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify and analyze factors implicated in the variability of the metabolic and growth responses to rhGH treatment in children born SGA |  | every three months during twenty seven months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic effects of rhGH treatment will be evaluated by body mass index (BMI) |  | every three months during | 
| Polymorphisms of different genes of the signaling pathway of GH and insulin |  | the day of inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin resistance, Growth hormone, Child, metabolic syndrome X, children born small for gestational age