Improved Mobility With Metformin in Patients With Myotonic Dystrophy Type 1

A Randomized Controlled Trial

Guillaume Bassez; Etienne Audureau; Jean-Yves Hogrel; Raphaëlle Arrouasse; Sandrine Baghdoyan; Hamza Bhugaloo; Marie-Laurence Gourlay-Chu; Philippe Le Corvoisier; Marc Peschanski


Brain. 2018;141(10):2855-2865. 

In This Article

Materials and Methods

Study Design

MYOMET was designed as a 52-week monocentric, double-blind, placebo-controlled phase II randomized study that aimed at assessing the efficacy of metformin on ambulation in patients with myotonic dystrophy type I. Secondary objectives were to evaluate safety of metformin and its potential efficacy on myotonia, muscle strength, gait variables, quality of life and splice defects. Patients were recruited from the cohort assessed in the Paris area neuromuscular reference centre. The entire clinical trial was conducted at the Henri-Mondor Hospital (Créteil, France), in the clinical research centre and the neuromuscular reference centre. Study protocol was approved by an appropriate ethics committee (CPP IDF VI, Paris, France, approval date 4 September 2013) and by the French regulatory authority (ANSM; Number 130862–31, approval date 13 August 2013). All participants were provided with participant information and responded with written informed consent to participate. This clinical trial was conducted in compliance with the Declaration of Helsinki and according to the Good Clinical Practice (GCP) and was registered in the European Union Clinical Trials Register (EudraCT Number 2013–001732-21; before the first inclusion of a patient.


Included patients had a diagnosis of DM1 confirmed by genetic mutation, were aged between 18 and 60 years inclusive, and covered by a national health insurance scheme affiliated to the French healthcare system. They had a Muscular Impairment Rating Scale (MIRS) (Mathieu et al., 2001) score equal to 2 or 3, were ambulatory and able to perform the 6MWT. Female participants of child-bearing potential were not included in case of pregnancy evidenced by a urinary test at the screening visit and were asked to use one effective method of birth control during the conduct of the study. Exclusion criteria included: evidence of serious concomitant or past history of medical disorders, including, but not limited to renal dysfunction, liver impairment, uncontrolled cardiac diseases, or any other medical conditions that might significantly impact ambulation. Patients under legal protection were excluded as well as those with current or past history of psychiatric conditions, including, but not limited to psychosis, suicidal ideations, or major depression. Known contra-indications to metformin were considered and treatment by medications intended for the treatment of DM1 were not allowed, including glucocorticoids, anabolic steroids, testosterone, growth hormone, or insulin-like growth factor 1 (IGF1) within 1 year of entry into the study and throughout the study participation. At the end of the 52-week study period, all patients having completed the randomized period were invited to enter an open-label extension phase during which they received the active treatment according to the same dose escalation performed at the study entry, and without any therapy restriction for the treatment of DM1. The open-label phase was still ongoing at the time of manuscript submission.

Randomization and Masking

Enrolled patients were randomly assigned (1:1; 20 patients per group) to either metformin therapy or a placebo, using a centralized randomization procedure. Upon satisfaction of all inclusion and exclusion criteria for patients who consented, the investigator sent the enrolment form to the Clinical Research Organization (CRO, Axonal-Biostatem, Nanterre, France) and in return received the assigned treatment arm. The computer-generated random allocation sequence was generated by the CRO prior to the onset of the study and concealed from participants and investigators. Randomization was stratified according to age (> or ≤ 50 years), gender and distance walked over 6 min (> or ≤500 m) at the screening visit. Patients were not informed of their treatment regimen and a matching placebo was manufactured (Bertin Pharma) to be identical to the metformin tablets in order to ensure the double-blind methodology. All study staff involved in the assessment of patient outcomes, including performance of the 6MWT, were blinded to the treatment group allocation. The blinding was maintained throughout the study period until both data entry and data processing were completed.


To prevent tolerance issues, participants received escalating daily doses of treatment over a 4-week period, up to the total study dose of 3000 mg/d. This dose was maintained for 48 weeks until the end of the study, cumulating a 52-week treatment duration. Metformin/placebo was taken orally by the patients, three times a day during or after a meal. After the enrolment of the first five patients of each arm, a blinded assessment of the tolerance was performed in order to check the patients' compliance to the study treatment and to take appropriate measures if required. The patients who did not enter in the open-label extension phase were followed for safety up to 4 weeks after the end of the treatment or after having discontinued all study medication.

A screening visit was conducted to check for eligibility criteria, including performance on the 6MWT. After patients were enrolled at the inclusion visit [Day 1 (D1)], follow-up visits were scheduled at Weeks 2, 4, 16, 28, 40 and 52 (W2, W4, W16, W28, W40 and W52). Details concerning follow-up of patients are available in Supplementary Table 1. Data collection included results from clinical evaluation (medical history, height, weight, body temperature, heart rate, respiratory rate and blood pressure), ECG, blood laboratory evaluation [including full blood count, liver function tests, renal function tests, electrolytes, glycaemia, lipase, amylase, calcium, creatine kinase (CK), INSR and ATP2A1 mRNAs], ambulation evaluation (6MWT), the activity and social participation DM1-Active scale (Hermans et al., 2015) and the health-related quality of life InQoL questionnaire. The InQoL questionnaire was scored according to published recommendations covering the following 12 subdomains: weakness, muscle locking, pain, fatigue, activities, independence, social relationships, emotions, body image, perceived and expected treatment effects, and overall neuromuscular disease-related quality of life.

Quantitative muscle testing was performed using a handheld dynamometer (Mark-10) for knee extension, finger extension and elbow flexion and using the MyoAnkle dynamometer for ankle flexion and extension (Moraux et al., 2013). Grip strength and myotonia were assessed using a grip dynamometer (MIE) during the MyoTone test (Hogrel, 2009). Accelerometric data were recorded along the three axes of space using a specific device (Locometrix©) during the 6MWT. The Locometrix© includes three accelerometers in a small (20 × 40 × 80 mm) and light (50 g) box and a data logger. The apparatus is incorporated into a semi-elastic belt, which is fastened around the subject's waist, close to the centre of gravity. Signals were recorded at a sampling frequency of 100 Hz. The recorded signals were transferred to a computer and analysed using dedicated software. Several gait variables were then computed: walking velocity, stride frequency and length, symmetry and regularity indexes, mechanical power. The power was computed in each space direction as the integral of the Fourier transform of the three acceleration signals. This variable measures the mean mechanical power generated in each direction of the device near the centre of gravity of the body and is expressed in W/kg. Its value depends on both the amplitude and the speed of the movements. It can be taken clinically as reflecting body abilities to move. The computation of all variables is further detailed in previous articles (Barthelemy et al., 2009; Mignardot et al., 2014).

Quantification of splice defects on blood samples were performed for identifying potential changes due to the treatment in the isoforms ratios of two genes known to exhibit splice defects in DM1 patients, namely INSR ± exon 11 and ATP2A1 ± exon 22. Conventional reverse transcription polymerase chain reaction (RT-PCR) and quantitative RT-PCR were used. Conventional RT-PCR techniques used were as previously described (Laustriat et al., 2015). Quantitative PCR performed in 384-well plates used a QuantStudio™ 12 K Flex Real-Time PCR System (Applied Biosystems, ThermoFisher Scientific) with Luminaris Probe qPCR Master Mix (Invitrogen) and TaqMan® gene expression assays: INSR − exon 11: Hs00965956_m1; INSR + exon 11: Hs00169631_m1; and 18 S : Hs99999901_s1 (Invitrogen). For ATP2A1 ± exon 22 transcript analysis, the following primers and MGB probe were used: ATP2A1 − exon 22: 5′-CGGAACTACCTAGAGGATCCAG-3′, 5′-CACAGCTCTGCCTGAAGATG-3′ and FAM-GGAAGTGAGCATCCTTTTGC-MGB NFQ; ATP2A1 + exon 22: 5′-GGGGGAACAGTTATCCCTCT-3′, 5′- ACCTCACCCAGTGGCTCAT-3′ and FAM-TTCGTTGCTCGGAACTACCT-MGB NFQ. A mesenchymal stem cell sample reference was included in all 384-well plates for amplification efficiency determination and as a calibrator for normalization. The method described by Pfaffl (2001) was used to determine the relative expression level of each gene.


The primary outcome was the mean difference in the distance walked as measured by the 6MWT between the baseline and Week 52 between the study groups. The test was performed according to the American Thoracic Society guidelines (ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories, 2002).

Secondary outcome measures were: changes from baseline to Week 16 and Week 28 in the distance walked at the 6MWT, changes from baseline in the distance walked at the 6MWT expressed as Z-scores according to available references in general population (Casanova et al., 2011), splice defects, muscle function and strength, gait variables, social participation and quality of life. The safety of metformin was evaluated by the overall incidence of adverse events and serious adverse events as well as ECG and laboratory assessments.

Adverse Events

Metformin has a long track record for treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycaemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose. Metformin is associated with a very low incidence of lactic acidosis. The product resume of metformin was used as a reference of suspected adverse events, and intensity of an event was evaluated by WHO definitions of serious adverse event (SAE) and suspected unexpected serious adverse reaction (SUSAR). Participants were informed about the risk of side effects before inclusion. During the trial, inconvenience experienced by the participants was registered in the diary and participants were interviewed about adverse events at evaluations. Trial continuation was stopped in individuals in whom a suspected serious adverse event of metformin was encountered.

Statistical Analysis and Sample Size Calculation

Available data are scarce regarding the expected impact of treatments on ambulation as assessed by the 6MWT in patients with myotonic dystrophy type I. In a randomized controlled trial assessing the impact of a physical exercise programme on ambulation in patients with MIRS scores of 2 to 5, Kierkegaard et al. (2011) reported a 2% increase in the intervention group [+9 m (standard deviation, SD 38)] whereas no increase was observed in the control group [−2 m (SD 40)]. Data from another previous report indicate that MIRS 2–3 patients are expected to have a mean walking distance of 550 m (SD 100) at baseline 6MWT (Kierkegaard and Tollback, 2007). Based on the previous figures and at two-sided type 1 error of 5%, a sample size of 30 patients (15 per group) was required to provide an 80% power to detect a minimally clinically important difference of +35 m (SD 35) in favour of the experimental group, representing a relative increase of +6% in distance walked between baseline (D1) and final visit (Week 52). Enrolment of a total of 40 patients (20 patients in each group) was thus planned, assuming a 25% dropout rate, as observed in previous studies with DM1 patients (Kierkegaard et al., 2011).

Descriptive results are presented as means with SD or median [interquartile range (IQR)] for continuous variables, and as numbers with percentages for categorical variables. Unadjusted comparisons of continuous variables (including the primary endpoint) were performed using t-tests or Mann-Whitney tests, depending on the normality of the variable distributions as assessed by the use of the Shapiro-Wilk test for normality along with the assessment of kurtosis and skewness indicators. Comparisons of categorical variables were performed using the χ 2 or Fisher's exact test, as appropriate. Comparisons between baseline and final assessments within groups were conducted using paired t-test or Wilcoxon signed ranks test, as appropriate.

For the primary outcome of the comparison of Week 0 with Week 52 for the 6MWT, patients were assessed according to randomized treatment group using an intent-to-treat (ITT) analysis and missing data imputation by the chained equations multiple imputation method. Supportive sensitivity analyses were performed to test the robustness of the results: (i) where the data were the complete set without imputing missing data; (ii) in 'per protocol' (PP) analysis after excluding patients with deviations to protocol; (iii) using linear multivariate regression models adjusted for variables used for stratification at randomization; and (iv) where the analysis was based on longitudinal data analysis using multiple linear mixed models to account for the correlation between repeated measures over time.

All tests were two-tailed and P-values < 0.05 were considered statistically significant. Analyses were pre-specified in the trial protocol. The analysis plan was performed using Stata v14.2 statistical software (StataCorp, College Station, TX, USA).

Data Availability

Researchers wishing to access the data collected in the MYOMET study are welcome. They are requested to contact Dr Marc Peschanski ( and sign a data access agreement.