Metformin in Obese Children and Adolescents

Study Overview
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Brief Summary
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The purpose of this study is to determine whether metformin is effective in reducing BMI and insulin resistance in obese children and adolescents.

Detailed Description
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The prevalence of obesity in children and adolescents is increasing rapidly and is associated with significant medical and psychosocial consequences persisting into adulthood. Obesity may lead to metabolic complications, such as insulin resistance, which can progress via impaired fasted glucose and impaired glucose tolerance to type 2 diabetes mellitus (T2DM) and to the development of micro- and macro-vascular complications. Metformin, an oral anti-diabetic licensed for T2DM for adults and children from 10 years onwards, is already used off label in obese children and adolescents with insulin resistance, even though the specific effects of metformin in these obese children and adolescents have not been elucidated, particularly upon long-term use. The rationale for this study is based on the hypothesis that metformin may reduce body mass index (BMI), insulin resistance and percentage of body-fat in obese children and adolescents with insulin resistance. Further more it is anticipated that metformin may delay the progression to T2DM and thereby micro- and macro-vascular complications in obese children and adolescents with insulin resistance.

Official Title
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An Efficacy, Safety and Pharmacokinetic Study on the Short-term and Long-term Use of Metformin in Obese Children and Adolescents

Conditions
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Obesity, Insulin Resistance

Intervention / Treatment
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* Drug: Metformin
* Behavioral: Lifestyle intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 10 and ≤ 16 years at study entry Caucasian descent Obesity defined as BMI-SDS > 2.3 Insulin resistance defined as HOMA-IR ≥ 3.4. An obtained informed consent from subjects and parents/caregivers. Exclusion Criteria: Presence of T2DM (American Diabetes Association criteria) Presence of endocrine disorders with steroid therapy Suspicion of polycystic ovarium syndrome; Height < -1.3 SD of target height; Syndrome disorders with or without mental retardation; Use of anti-hyperglycaemic drugs; Pregnancy (pregnancy test will be performed, if applicable); (History of) alcohol abuse; Impaired renal and/or hepatic function (defined as GFR < 80 ml/min. GFR=40 x length (cm) / serumcreatinin (μmol/l and ALAT >150% of normal value for age); Use of ritonavir; use of ACE inhibitors; Insufficient knowledge of the Dutch language.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 16 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin<br>Metformin with lifestyle intervention during 18 months | Drug: Metformin<br>* Oral administration, 500 mg daily at week 1. Every week metformin dosage increases with 500 mg, to a maximum dose of 1000 mg bid. This maximum dose will be administered till the end of the study.<br>* Other names: Glucophage;Behavioral: Lifestyle intervention<br>* Lifestyle intervention: 18 months physical therapy and dietary advice<br>|
| Placebo Comparator: Placebo<br>Placebo and lifestyle intervention during 18 months | Behavioral: Lifestyle intervention<br>* Lifestyle intervention: 18 months physical therapy and dietary advice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in BMI from baseline | Change in BMI after part 1 (double blind) and part 2 ( follow-up) | 18 months and 36 months | 
| Change in Insulin resistance from baseline | calculated by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal and hepatic function | creatinine and alat | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | 
| Tolerability | The amount of reported adverse effects, in relation to the achieved dose level. | 3; 6; 9; 12; 15; 18; 24; 30 and 36 months | 
| Pharmacokinetics (PK)-parameters: clearance (ml/min) | Clearance where applicable expressed per body weight, age category, Tanner Stage and gender, clearance will be determined with a two-compartment pharmacokinetic model using non linear mixed effect modelling. | 9 months | 
| Body fat percentage |  | 0, 9, 18 and 36 months | 
| Physical fitness |  | 0, 9, 18 and 36 months | 
| Quality of life |  | 0, 9, 18 and 36 months | 
| Long term efficacy | Based on BMI and HOMA-IR values | 36 months | 
| Long-term safety | Renal and hepatic function after 36 months of metformin use | 36 months | 
| Long-term tolerability | The amount of adverse effects after 36 months | 36 months | 
| Microvascular complications | Measured as micro-albuminuria | 36 months | 
| Macrovascular complications | Measured with Pulse Wave Velocity and Augmentation Index. | 36 monthts | 
| Development of T2DM |  | 36 months | 
| PK-parameters: volume of distribution (liters) | Volume of distribution, where applicable expressed per body weight, age category, Tanner Stage and gender, volume of distribution will be determined with a two-compartment pharmacokinetic model using non linear mixed effect modelling. | 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obesity, Children, Adolescents, Metformin, Insulin resistance