E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
obese children and adolescents of Caucasian descent with insulin resistance in the age of ≥ 10 and ≤ 16 years at study entry. |
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E.1.1.1 | Medical condition in easily understood language |
insulin resistance due to obesity in children and adolescents |
ongevoeligheid voor insuline ten gevolge van ernstig overgewicht. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the METFORMIN study is to determine the efficacy of metformin in combination with lifestyle-intervention in obese children and adolescents with insulin resistance versus placebo with lifestyle-intervention. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the METFORMIN study is to determine the safety and tolerability of metformin in combination with lifestyle-intervention in obese children and adolescents with insulin resistance versus placebo with lifestyle-intervention.
The tertiary objective of the METFORMIN study is to study the population pharmacokinetics (PK) of metformin in obese children and adolescents.
The quaternary objective of the METFORMIN study is to determine the long-term efficacy and long-term safety and tolerability of metformin in obese children and adolescents with insulin resistance.
Other objectives are to compare values of body fat measured using bio-impedance with values of body fat measured using dual energy X-ray absorptiometry (DEXA scan), and to compare insulin sensitivity measured by the whole body insulin sensitivity index (WBISI) with insulin sensitivity calculated by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) in obese children and adolescents.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The inclusion criteria are subject’s age ≥ 10 and ≤ 16 years at study entry, from Caucasian descent, with obesity defined as BMI-SDS > 2.3 and with insulin resistance defined as HOMA-IR ≥ 3.4. In addition an obtained informed consent from subjects and parents/caregivers.
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E.4 | Principal exclusion criteria |
The exclusion criteria are 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary study endpoint for efficacy is the reduction in BMI, which is calculated from the anthropometric measurements. Other primary endpoints for efficacy are insulin resistance, calculated by the HOMA-IR, percentage of body fat measured by bio-impedance, HbA1C, β-cell function, calculated by HOMA-β%, oral disposition index, insulin secretion calculated by the insulinogenic index, physical fitness measured by validated fitness tests and quality of life measured by validated quality of life questionnaire.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of primary study point will be performed at t=18 months and t=36 months |
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E.5.2 | Secondary end point(s) |
Secondary outcome parameters for safety of metformin treatment are hepatic and renal function tests, and for tolerability the number of adverse effects (in relation to the achieved dose level).
Tertiary outcome parameters are the PK parameters of metformin in obese children and adolescents. These parameters are estimated using population PK-PD modelling techniques in which a comprehensive covariate analysis will be performed allowing to account for variability in PK parameters on the basis of individual characteristics such as age, bodyweight, BMI, percentage of body fat, gender, Tanner stage and genetic constitution.
Quaternary outcome parameters for long-term efficacy and long-term safety and tolerability of metformin are BMI, insulin resistance calculated by the HOMA-IR, percentage of body fat measured by bio-impedance, HbA1C, β-cell function, calculated by HOMA-β%, oral disposition index, insulin secretion calculated by the insulinogenic index, physical fitness measured by validated fitness tests, quality of life measured by validated quality of life questionnaire, hepatic and renal function tests and number of side effects. In addition, the percentage of patients that has developed impaired fasted glucose, impaired glucose tolerance (2-hrs plasma glucose during an OGTT), T2DM and the development of micro-vascular complications detected by micro-albuminuria and macro-vascular complications detected by using pulse wave velocity (PWV) and augmentation index (AIx) is evaluated.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of secondary endpoint parameters will be performed at t=18 months and t=36 months
Evaluation of teriary endpoint parameters will be performed at t=18 months
Evaluation of quaternary endpoint parameters will be performed at t=36 months
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the last patient's visit. See section 11.4 of the protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |