Metformin in Obese Children and Adolescents (MetVoorMin)

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

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

Study Overview

• Status: Completed
• Conditions: Obesity; Insulin Resistance
• Intervention / Treatment: Drug: Metformin; Behavioral: Lifestyle intervention

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 Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • 's Hertogenbosch, Netherlands
    • Jeroen Bosch Hospital
  • Nieuwegein, Netherlands, 3430EM
    • St. Antonius Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; Metformin with lifestyle intervention during 18 months	Drug: Metformin; 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.; Other Names: Glucophage; Behavioral: Lifestyle intervention; Lifestyle intervention: 18 months physical therapy and dietary advice
Placebo Comparator: Placebo; Placebo and lifestyle intervention during 18 months	Behavioral: Lifestyle intervention; Lifestyle intervention: 18 months physical therapy and dietary advice

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St. Antonius Hospital
• Collaborators: Jeroen Bosch Ziekenhuis
• Investigators: Principal Investigator: Marja MJ van der Vorst, MD, PhD, St. Antonius Hospital

Publications and helpful links

General Publications

• van Rongen A, van der Aa MP, Matic M, van Schaik RHN, Deneer VHM, van der Vorst MM, Knibbe CAJ. Increased Metformin Clearance in Overweight and Obese Adolescents: A Pharmacokinetic Substudy of a Randomized Controlled Trial. Paediatr Drugs. 2018 Aug;20(4):365-374. doi: 10.1007/s40272-018-0293-1.
• van der Aa MP, Hoving V, van de Garde EM, de Boer A, Knibbe CA, van der Vorst MM. The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial. J Obes. 2016;2016:7852648. doi: 10.1155/2016/7852648. Epub 2016 Dec 22.
• van der Aa MP, Elst MA, van Mil EG, Knibbe CA, van der Vorst MM. METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study. Trials. 2014 Jun 5;15:207. doi: 10.1186/1745-6215-15-207.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: October 20, 2011
• First Submitted That Met QC Criteria: December 6, 2011
• First Posted (Estimate): December 8, 2011

Study Record Updates

• Last Update Posted (Actual): April 27, 2017
• Last Update Submitted That Met QC Criteria: April 26, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Adolescents; Obesity; Insulin resistance; Children; Metformin
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: Metformin 2011-6; 2010-023980-17 (EudraCT Number)