Metformin in Obese Children and Adolescents

Phase 3

Completed

• Conditions: Obesity; Insulin Resistance
• Interventions: Drug: Metformin; Behavioral: Lifestyle intervention

• Registration Number: NCT01487993
• Lead Sponsor: St. Antonius Hospital

Brief Summary

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

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 Timeline

• Study Start: 2011-08
• Study First Submitted: 2011-10-20
• Study First Submitted QC: 2011-12-06
• Study First Posted: 2011-12-08
• Primary Completion: 2015-08
• Study Completion: 2017-02-28
• Status Verified: 2017-04
• Last Update Submitted: 2017-04-26
• Last Update Posted: 2017-04-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metformin	Metformin	Metformin with lifestyle intervention during 18 months
Metformin	Lifestyle intervention	Metformin with lifestyle intervention during 18 months
Placebo	Lifestyle intervention	Placebo and lifestyle intervention during 18 months

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Renal and hepatic function	3; 6; 9; 12; 15; 18; 24; 30 and 36 months	creatinine and alat
Tolerability	3; 6; 9; 12; 15; 18; 24; 30 and 36 months	The amount of reported adverse effects, in relation to the achieved dose level.
Long term efficacy	36 months	Based on BMI and HOMA-IR values
Long-term safety	36 months	Renal and hepatic function after 36 months of metformin use
Microvascular complications	36 months	Measured as micro-albuminuria
Macrovascular complications	36 monthts	Measured with Pulse Wave Velocity and Augmentation Index.
Development of T2DM	36 months
PK-parameters: volume of distribution (liters)	9 months	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.
Pharmacokinetics (PK)-parameters: clearance (ml/min)	9 months	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.
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 tolerability	36 months	The amount of adverse effects after 36 months

Trial Locations

Locations (2)

Jeroen Bosch Hospital; 🇳🇱 's Hertogenbosch, Netherlands

St. Antonius Hospital; 🇳🇱 Nieuwegein, Netherlands