Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol
Por:
Bassols-Casadevall J, de Zegher F, Díaz-Silva M, Carreras-Badosa G, García-Beltran C, Puerto-Carranza E, Oliver-Vila C, Casano-Sancho P, Franco CA, Malpique R, López-Bermejo A and Ibañez-Toda L
Publicada:
24 ene 2023
Ahead of Print:
24 ene 2023
Resumen:
BackgroundA "mismatch" sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in "mismatch" girls with early puberty.MethodsRandomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0-9.3 years; birthweight (BW) for gestational age in lower tertile (-1.96< Z-score <-0.44), body mass index (BMI) in upper tertile (+0.44< Z-score < +1.96) and early progressive puberty (Tanner B2 at 7.7-9.0 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in "mismatch" adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0-1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat.DiscussionThe present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight.
Filiaciones:
Bassols-Casadevall J:
Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
de Zegher F:
Leuven Research & Development, University of Leuven, Leuven, Belgium
Díaz-Silva M:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain
Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
Carreras-Badosa G:
Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
García-Beltran C:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain
Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
Puerto-Carranza E:
Pediatrics, Dr. Josep Trueta Hospital, Girona, Spain
Oliver-Vila C:
Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
Casano-Sancho P:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain
Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
Franco CA:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain
Malpique R:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain
Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
López-Bermejo A:
Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
Pediatrics, Dr. Josep Trueta Hospital, Girona, Spain.
Department of Medical Sciences, University of Girona, Girona, Spain.
Ibañez-Toda L:
Endocrinology Department, Pediatric Research Institute Sant Joan de Deu, University of Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
Green Accepted, Green Submitted, gold
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