Evaluation of the Efficacy and Safety of Metformin in the Myotonic Dystrophy Type 1 (Steinert's Disease)

Overview

The study team hypothesize that non-diabetic patients with Myotonic dystrophy type I (DM1) will improve their symptoms, especially their motor deficit which is the main feature of the disease, because of the splicing defect correction by metformin. The primary objective of the study is to evaluate the efficacy of metformin vs placebo, on the improvement of muscle function in patients with DM1 compared to its placebo. As the secondary objectives, the study aims: * To evaluate the safety of metformin on patient with DM1. * To evaluate the efficacy of metformin vs placebo on: 1. The hand-grip strength; 2. The thumb-index pinch strength; 3. The locomotor function; 4. The respiratory function; 5. The cardiac function; 6. The quality of life; 7. The daily and social activity.

This is a multicenter, national, comparative study comparing the efficacy and safety of metformin and placebo in patients (1:1 ratio between the 2 groups) with DM1. Population of study participants: patients with biochemically and/or genetically confirmed DM1 disease already followed in the referral and competence departments, as well as new patients. All patients will be included by a neuromuscular specialist from French centers participating in the research. Enrolled patients were randomly assigned (71 patients per group with 1:1 ratio) to either metformin therapy or a placebo, using a centralized randomization procedure. Metformin or placebo will be administered orally and titrated as recommended in diabetic patients. Initial digestive effects (nausea, vomiting and constipation) of metformin that can be observed in the first days. If digestive tolerance is good, treatment will be increased to a maximum of 1000 mg three times a day i.e. 3000 mg/day after another week. In case of bad digestive tolerance, the dosage should be decrease and the maximum tolerated dosage of metformin should be used. The evaluations of muscle function, walking test, respiratory and cardiac function, quality of life, and tolerance will be assessed at M6 and M12, in the neuromuscular centers. With the estimated effect size, we believe that the inclusion capacities evaluated at 8 to 12 patients per center over one year (18 reference centers involved) will allow to determine a significant difference of MFM score 12 months after inclusion. Dose titration, monitoring of side effects and dose adjustments will be assessed at each visit according to the site endocrinologist advice, if necessary. Statistical analysis: The difference between the score at 12 months and baseline will be compared between treatment groups using the Student T-test. Secondary efficacy endpoints evaluating the evolution of symptoms will be analyzed using either a GMM or a GEE for continuous and categorical variables, respectively. Other quantitative variables will be compared using the Student t-test (or a non-parametric test if the distribution remains skewed following transformation), while categorical variables will be analyzed using either the Chi-squared or the Fisher-exact tests. All efficacy endpoints will be analysed on an intention-to- treat basis and safety endpoints on a per-protocol basis. All statistical tests will be performed with a level of significance of 5%. No interim analysis will be performed.