Metformin therapy to improve adult height prognosis in growth hormone deficient children treated with growth hormone: a clinical trial intervention

Català Besa, Mireia
Background: Growth hormone (GH) deficient children treated with GH experience a gain in adult height prognosis. However, there are a number of patients who may advance their bone age more rapidly that their height gain, which may worsen their adult height prognosis. Moreover, GH treatment causes a secondary hyperinsulinemic state that could increase the cardiovascular risk in treated children in the long-term. Justification: In non GH-deficient children, studies has shown that metformin causes an improvement in height in children treated with high doses and larger periods of time, especially those with insulin resistance at baseline. These effects may be mediated by metformin actions improving insulin sensitivity and inhibiting aromatase activity and the synthesis of oestrogen (the agent responsible for bone age advancement). On the basis, metformin could improve adult height prognosis and could also ameliorate the insulin resistance state caused by GH treatment in these patients. Main objective: The goal of the present work is to determine if metformin use in combination with GH therapy, can potentiate its growth effects and improve adult height prognosis in GH-deficient children with poor adult height prognosis in comparison to GH plus placebo treatment. Design: This protocol is for a multicentre, prospective, phase III/IV, randomized, double blind, placebo controlled, 4-year duration clinical trial in GH-deficient children treated with GH and poor adult height prognosis. Participants: Prepubertal Caucasian isolated GH-deficient children aged 8-10 years treated with GH for at least 2 years with average GH doses (between 0.025-0.035 mg/kg/day) who have poor adult height prognosis (between -1.0 SDS and -3.0 SDS) recruited at the Pediatric Endocrinology Unit at both Hospital Doctor Josep Trueta of Girona and Hospital Sant Joan de Déu of Barcelona. Main outcome variable: Adult height prognosis at the start and the end of GH treatment (Bailey-Pinneau method). Method:s 120 Isolated GH-deficient children treated with GH and poor adult height prognosis will be randomised into treatment or placebo group (1:1) and will be stratified by age, gender and BMI. As an intervention treatment, they will receive a single oral dose of metformin or placebo of 425 mg/day for the first 2 years and a single oral dose of metformin or placebo of 850 mg/day for the last 2 years. Patients will be assessed every 6 months at regular visits scheduled for follow-up of their GH treatment until the study finishes. Data analysis: Data analysis will be performed using SPSS version 22.0. Results for major variables will be performed using Mann-Whitney test (continuous variables) and Fisher exact test (categorical variables). The analysis of response to treatment for endpoints variables will be performed by general linear model (GLM) for repeated measures. A p value <0.05 will be considered statistically significant ​
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