Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol

Trials

Study Protocol

Céline Alicia Franco¹  Paula Casano²  Marta Diaz²  Cristina Garcia-Beltran²  Lourdes Ibáñez²  Rita Malpique²  Francis de Zegher³  Judit Bassols⁴  Gemma Carreras-Badosa⁵  Cora Oliver-Vila⁵  Abel López-Bermejo⁶  Elsa Puerto-Carranza⁷ 

[1] Endocrinology Department, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Endocrinology Department, Pediatric Research Institute Sant Joan de Déu, University of Barcelona, Barcelona, Spain;Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain;Leuven Research & Development, University of Leuven, Leuven, Belgium;Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain;Pediatric Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Girona, Spain;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;Pediatrics, Dr. Josep Trueta Hospital, Girona, Spain;

关键词: Prenatal weight gain;    Postnatal weight gain;    Early puberty;    Early menarche;    PCOS;    Ectopic fat;    Bone maturation;    Spironolactone;    Pioglitazone;    Metformin;   

DOI  :  10.1186/s13063-022-07050-w

 received in 2022-10-18, accepted in 2022-12-23,  发布年份 2022

来源: Springer

【 摘 要 】

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.Trial registrationEudraCT 2021-006766-21. Registered on May 30, 2022.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 1

12888_2022_4500_Article_IEq1.gif