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

Disclosures

Brain. 2018;141(10):2855-2865. 

In This Article

Results

Forty-eight patients were identified by the mean of the DM-scope registry when applying study inclusion and non-incluion criteria. Eight patients were declared non-eligible due to test results: prolonged PR interval (>200 ms) at ECG in two, and elevated liver enzyme in serum (>1.5 N upper value) in five. Forty patients were thus included and randomized between February 2014 and May 2015, of whom 38 received at least one dose of treatment and were considered in the ITT population. Twenty-nine completed the 1-year follow-up (ITT complete cases), among whom 23 had no major deviation to protocol [per protocol (PP) population; Figure 1]. Of the 15/38 patients excluded from the original ITT population, 10 were in the treated group and five had received placebo. More precisely, two patients were excluded because of dispensing errors of drugs; five patients in the treated and four patients in the placebo groups were lost because of deviation to protocol or lack of compliance. Four additional patients in the treated group withdrew between the pretreatment and the first post-treatment evaluations because of metformin-induced gastrointestinal adverse events that were not well controlled by usual anti- diarrhoeic treatment. Baseline characteristics of patients did not substantially differ between the two groups in either ITT (Table 1) or per protocol populations (Supplementary Table 2). All patients in the ITT group reached the maximal 3 mg/day dosage of metformin.

Figure 1.

Flowchart of the study populations. PP = per protocol population.

Primary Outcome

Results concerning the primary outcome are shown in Table 2. Altogether, the placebo group showed very stable values between baseline and the Week 52 examination. In contrast, the metformin-treated group systematically showed a trend to increase in performance, by whichever analysis carried out. Within-group analyses identified a statistically significant progression in the metformin group in the per protocol analysis (n = 9, P = 0.017). The difference between the treated and placebo groups in mean change in the total distance for 6MWT was statistically significant when considering patients who entirely fulfilled the protocol [per protocol, n = 23; control +3.7 m (±32.4); metformin +32.9 m (±32.7); difference in change +29.2 m, P = 0.048]. Modified-ITT analysis of the whole sample did not reach significance level despite systematically higher change estimates in the metformin group, whether after multiple imputation of missing values [n = 38; Control mean change +2.6 m (±8.2); metformin +20.5 m (±13.1); difference in change +17.9 m, P = 0.255], or considering only patients with complete information for the 6MWT [n = 29; Control +3.1 m (±31.2); metformin +14.6 m (±47.6); difference in change +11.5 m, P = 0.441].

Intermediate visits for the primary outcome at 16 and 28 weeks follow-up yielded similar trends, with a statistically significant improvement in the metformin group in per protocol analysis as early as the Week 16 visit [Control +3.6 m (±17.6); metformin +32.6 m (±36.9); difference in change +28.9 m, P = 0.019; Figure 2 and Supplementary Figure 1].

Figure 2.

6MWT evolution across follow-up visits: changes from baseline in per protocol (n = 23) and ITT (n = 38) populations. Results are shown as boxplots, with each box representing the IQR (first to third quartile), the line within the box indicating the mean, and the whiskers extending to 1.5 times the IQR above and below the box; the dots represent individual values for each patient.

Supplemental Figure 1.

6MWT evolution across follow-up visits: total distance in Per Protocol (PP, N=23) and ITT (N=38) populations. Results are shown as boxplots, with each box representing the interquartile range (1st to 3rd quartile, IQR), the line within the box indicating the mean, and the whiskers extending to 1.5 times the IQR above and below the box; the dots represent individual values for each patient.

Similar results were found after multiple adjustments on stratification variables, namely age, gender and baseline 6MWT [ITT: (metformin − control) difference in change+10.9 m, P = 0.491; per protocol: (metformin − control) difference in change +29.0 m, P = 0.055 and after using mixed models for longitudinal analysis of 6WMT values over time [interaction time × metformin group: ITT +0.03 m/day (95% confidence interval −0.04 to 0.10) P = 0.365; per protocol+0.07 m/day (−0.01 to 0.14), P = 0.077]. Analysis of age-sex standardized scores revealed decreased 6MWT Z-scores values compared to the general population [baseline (control) −1.84 SD; (metformin) −1.91 SD], with similar trends found for changes from baseline to those based on raw 6MWT values expressed in metres (Supplementary Table 3).

Secondary Outcomes

Results for the other secondary outcomes in ITT and per protocol populations are shown in Supplementary Table 4 and Supplementary Table 5. Almost all clinical parameters evolved similarly over time, whether patients were treated or not with metformin. This included, in particular, myotonia indices, muscle function and strength, quality of life and ECG. Biological samples were also not different between the two groups. As concerns splicing defects associated with DM1, namely INSR ± exon 11 and ATP2A1 ± exon 22, results of conventional RT-PCR were not interpretable because the minority isoforms were below detection levels (Supplementary Figure 2A). Quantitative PCR assays with greater sensitivity allowed us to detect the minority transcript INSR + exon 11 but at a barely visible level of detection. Variability of the measures precluded the determination of any statistically significant variation due to treatment (Supplementary Figure 2B).

Supplemental Figure 2.

Alternate transcripts of DM1-affected genes in the blood of patients. A. RT-PCR of three representative patients at inclusion showing only one transcript for INSR and ATP2A1, whereas a control MSC sample derived from an ES cell line derived from a gene-carrying embryo and the universal control both show an additional, minority transcript. B. Statistical analysis of Quantitative RT-PCR of INSR+/-11 transcripts ratio showing the lack of a significant difference between the two per protocol populations of patients at various times in the study.

Some gait parameters showed a statistically significant difference between the two groups (Table 3). The total mechanical power during gait was significantly increased in the treated group compared to the placebo group (P = 0.011). This was due to an increase in mechanical power in both the cranio-caudal (P = 0.011) and antero-posterior (P = 0.028) directions. In contrast, the other gait variables showed no change in either group during the study.

Safety

Overall, 280 adverse events were reported in 38 (100%) participants, including 163 in the metformin group and 117 in the control group, of which 68% were not considered to be related to the study treatment (metformin group 53%; control group 88%). Five serious adverse events were reported in four participants (10.5%), including three in the metformin group, and one in the control group (Supplementary Table 6). Most frequent adverse events were gastrointestinal disorders including diarrhoea (n = 15 in the treated group versus n = 5 in the placebo group), abdominal pain (n = 10 versus n = 6) and dyspepsia (n = 4 versus n = 0). Diarrhoea could be controlled to the level of patient's satisfaction using symptomatic treatments, except in four patients who withdrew from the study over the first trimester after inclusion. Asthenia occurred in eight participants in the metformin group and in three in the control group. Benign infections were more frequently observed in the control (n = 16) than in the metformin group (n = 9). Weight loss occurred in 11 participants, all in the metformin group, with a mean loss of −1.49 kg (±2.65) at Week 16 and −0.51 kg (±4.08) at Week 52 in the ITT population, −2.42 kg (±2.34) and −1.98 kg (±2.97) in the per protocol population. However, weight did not statistically differ between the two groups throughout the study. No effect of metformin was recorded on either ECG parameters or laboratory assessments, except for an intermittent increase of lipase in one participant. There was no case of hypoglycaemia or lactic acidosis in participants in the metformin group.

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