The purpose of this study is to determine whether metformin is effective in reducing BMI and insulin resistance in obese children and adolescents.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
62
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.
Lifestyle intervention: 18 months physical therapy and dietary advice
Jeroen Bosch Hospital
's-Hertogenbosch, Netherlands
St. Antonius Hospital
Nieuwegein, Netherlands
Change in BMI from baseline
Change in BMI after part 1 (double blind) and part 2 ( follow-up)
Time frame: 18 months and 36 months
Change in Insulin resistance from baseline
calculated by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR).
Time frame: 3; 6; 9; 12; 15; 18; 24; 30 and 36 months
Renal and hepatic function
creatinine and alat
Time frame: 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.
Time frame: 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.
Time frame: 9 months
Body fat percentage
Time frame: 0, 9, 18 and 36 months
Physical fitness
Time frame: 0, 9, 18 and 36 months
Quality of life
Time frame: 0, 9, 18 and 36 months
Long term efficacy
Based on BMI and HOMA-IR values
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Time frame: 36 months
Long-term safety
Renal and hepatic function after 36 months of metformin use
Time frame: 36 months
Long-term tolerability
The amount of adverse effects after 36 months
Time frame: 36 months
Microvascular complications
Measured as micro-albuminuria
Time frame: 36 months
Macrovascular complications
Measured with Pulse Wave Velocity and Augmentation Index.
Time frame: 36 monthts
Development of T2DM
Time frame: 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.
Time frame: 9 months