Effect of Insulin Sensitization on IGF-1 Response to Growth Hormone in SGA Children

Study Overview
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Brief Summary
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This study is aimed to determine if Metformin treatment in children born small for gestational age (SGA) who are being treated with Growth Hormone (GH) for short stature improves the response to GH by producing greater concentrations of Insulin-like growth factor -1 (IGF-1) in the blood.

Detailed Description
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Growth hormone treatment (GH) is recommended in children born small for gestational age (SGA) who fail to catch-up. SGA is a heterogeneous condition as reflected in the varied response to GH treatment. Variable generation and resistance to Insulin-like growth factor-1 (IGF-1), the most important circulating mediator of GH action may underpin this heterogeneity. An association between the variants in the genes related to lower insulin sensitivity and reduced IGF-1 and growth response to GH therapy in SGA children have been reported recently. The hypothesis of this study is that insulin sensitivity may be causally linked to the response to GH therapy, and adjuvant therapy with an insulin sensitizer may improve IGF-1 generation, decrease IGF-I resistance and optimise growth response. To explore this hypothesis, this study aims to determine the effects of insulin sensitization using Metformin as an adjuvant to a fixed dose GH therapy for 6 months in short SGA children. The patients will be short SGA children between age 4 -10 years and identified from three paediatric endocrine units in Denmark, Ireland and the United Kingdom. In this mechanistic study 24 subjects starting GH treatment will be randomised in a 1:1 ratio to adjunctive Metformin or placebo for 6 months and followed-up for another 6months. The participants will receive GH treatment for the entire duration of the study (12 months) and will undergo an oral glucose tolerance test and dual-energy x-ray absorptiometry scan to determine glucose metabolism and body fat mass respectively at baseline and 6 months, and will have 3 monthly measurements of height, weight and skinfold thickness. The primary outcome will be the area under the curve of IGF-1 levels measured at 0, 1, 3 and 6 months. Secondary outcomes will include changes in insulin sensitivity, height, body fat mass and safety measures at 6 and 12 months.

Official Title
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Effect of Insulin Sensitization on Insulin Like Growth Factor-1 Responses to Growth Hormone Treatment in Children Born Small for Gestational Age

Conditions
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Small for Gestational Age

Intervention / Treatment
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* Drug: Metformin
* Drug: Growth Hormone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SGA children eligible for GH treatment according to European Medicines Agency (EMA) and The National Institute for Health and Care Excellence (NICE) criteria Gestational age at birth >28 weeks Age 4-9 years in girls and 4-10 years in boys Prepubertal at start of treatment Naïve to GH therapy Exclusion Criteria: Known or suspected allergy to GH Previous participation in a GH trial Severe learning difficulties Previous or active malignancy Benign intracranial hypertension

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GH+Metformin<br>The children will be given both Growth Hormone and Metformin for 6 months | Drug: Metformin<br>* Metformin is administered as an oral solution<br>Drug: Growth Hormone<br>* Growth Hormone- no specific band<br>|
| Placebo Comparator: GH+Placebo<br>Children will be given both GH and Placebo for 6 months | Drug: Growth Hormone<br>* Growth Hormone- no specific band<br>Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IGF-1 response | Area under the curve of IGF-1 standard deviation scores over 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height velocity | Height increments | 6 months and 1 year | 
| Insulin sensitivity | Measured by homeostasis model assessment model | 6 months and 1 year | 
| Insulin secretion | Measured by oral glucose tolerance test | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Small for gestational age, insulin sensitivity, IGF-1 response, growth hormone treatment