Pastor-Villaescusa, BelénCaballero-Villarraso, JavierCañete, M DoloresHoyos, RaúlMaldonado, JoséBueno, GloriaLeis, RosauraGil, ÁngelCañete, RamónAguilera, Concepción M2016-08-092016-08-092016-07-18Pastor-Villaescusa B, Caballero-Villarraso J, Cañete MD, Hoyos R, Maldonado J, Bueno G, et al. Evaluation of differential effects of metformin treatment in obese children according to pubertal stage and genetic variations: study protocol for a randomized controlled trial. Trials. 2016; 17(1):323http://hdl.handle.net/10668/2321Journal Article; TRIAL REGISTRATION: Registered by European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011BACKGROUND Overweight and obesity are considered to be serious public health problems. In pediatric populations, insulin resistance, dyslipidemia, and hypertension associated with obesity occur with increased frequencies. Metformin is an oral anti-hyperglycemic agent that has been demonstrated to be efficacious in the treatment of diabetic and non-diabetic obese adults. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Additionally, potential microbiota-mediated mechanisms of metformin effect have been recently described. However, scant work has been conducted in children, with no attention being paid to the potential effects of pubertal development. Thus, the main objective of the present study is to evaluate the effect of metformin treatment together with lifestyle recommendations in a randomized control trial (RCT) of obese children according to pubertal stage, genetic variants and signature of gut microbiota. METHODS/DESIGN This is a randomized, prospective, double-blind, placebo-controlled, multicenter trial, which is stratified by puberty and sex. Eighty pre-pubertal (40 boys and 40 girls) and 80 pubertal non-diabetic obese children (40 boys and 40 girls) are being recruited in four Spanish Clinical Hospitals. The inclusion criteria to participate in the RCT include a Body Mass Index (BMI) above the 95th percentile and age 7-14 years. The pubertal stage is determined based on the Tanner criteria. Participants are assigned to two groups in accordance with a randomization schedule and receive 1 g of metformin or placebo for six months in combination with healthy lifestyle recommendations in both groups. The primary outcomes include changes in the BMI Z score and the biomarkers associated with the early appearance of insulin resistance syndrome, inflammation, cardiovascular risk according of the presence of genetic determinants of metformin response, as well as possible modifications in microbiota. DISCUSSION This study will assess the differential response of metformin treatment at six months in pre-pubertal and pubertal obese children. TRIAL REGISTRATION Registered by European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.enMetforminChildrenObesityPubertyLifestyle interventionMicrobiotaPolymorphismsNiñoMétodo doble ciegoDislipidemiasVariación genéticaHipoglucemiantesInflamaciónResistencia a la insulinaSíndrome X metabólicoMetforminaObesidadFarmacogenéticaEstudios prospectivosPubertadSalud públicaDistribución aleatoriaIndice de masa corporalMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Mass IndexMedical Subject Headings::Diseases::Cardiovascular DiseasesMedical Subject Headings::Named Groups::Persons::Age Groups::ChildMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes MellitusMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Double-Blind MethodMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Lipid Metabolism Disorders::DyslipidemiasMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic VariationMedical Subject Headings::Diseases::Cardiovascular Diseases::Vascular Diseases::HypertensionMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Hypoglycemic AgentsMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::InflammationMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin ResistanceMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Metabolic Syndrome XMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amidines::Guanidines::Biguanides::MetforminMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Size::Body Weight::Overweight::ObesityMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Size::Body Weight::OverweightMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective StudiesMedical Subject Headings::Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::PubertyMedical Subject Headings::Health Care::Environment and Public Health::Public HealthMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Random AllocationMedical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiota::Gastrointestinal MicrobiomeMedical Subject Headings::Disciplines and Occupations::Health Occupations::Pharmacology::Pharmacogeneticsresearch article27432166open access10.1186/s13063-016-1403-41745-6215PMC4950074