Mexiletin (1) – Namuscla®

• Clinical trials
  • The benefit assessment is based on the multicentre, randomised, double-blind, placebo-controlled, cross-over Phase III MYOMEX trial, which was conducted exclusively at study centres in France.

Adult patients with non-dystrophic myotonic disorders

• Overall, this indicates that Mexiletin offers a non-quantifiable additional benefit compared with placebo.
• mortality
  • No deaths occurred in the MYOMEX trial.
• Morbidity – VAS severity of muscle stiffness
  • The severity of muscle stiffness was assessed using a visual analogue scale (VAS).
  • The combined analysis of treatment effects across both treatment sequences shows a statistically significant and very marked treatment effect in favour of mexiletine compared with placebo.
  • Patient-reported muscle stiffness decreased by 41.7 mm on the VAS during treatment with mexiletine; in contrast, the reduction on the VAS during treatment with placebo was only 9.0 mm.
  • For the endpoint ‘VAS severity of muscle stiffness’, a statistically significant and, based on Hedges’ g calculations, clinically relevant difference in favour of treatment with mexiletine compared with placebo was also observed when both treatment periods were analysed separately.
• Quality of life – INQoL
  • Health-related quality of life was assessed using the Individualised Neuromuscular Quality of Life Questionnaire (INQoL).
  • In the combined analysis of both treatment sequences, a statistically significant and very marked treatment effect in favour of mexiletine over placebo was observed for the ‘Symptoms’ domain in the subdomains of muscle weakness, muscle spasm, pain and fatigue.
  • In the ‘quality of life’ domain, too, the combined analysis of both treatment sequences revealed a statistically significant, very marked treatment effect for mexiletine compared with placebo, both in overall quality of life and in the subdomains of activity, independence, social relationships, emotions and body perception – which underpin overall quality of life – a statistically significant and very marked treatment effect in favour of mexiletine compared with placebo.
  • For treatment period 1, Hedges’ g calculations for the ‘symptoms’ domain reveal clinically relevant differences for three of the four symptoms assessed (muscle stiffness, pain and fatigue).
  • For the ‘quality of life’ domain, Hedges’ g calculations indicate clinically relevant improvements in favour of mexiletine in four of the five subdomains (activity, independence, social relationships and emotions).
  • No adequate analyses are available for treatment period 2, as the pharmaceutical manufacturer reported baseline values which, according to the study protocol and study report, were not collected; consequently, no separate results or effect estimates are presented for this period.
• Side effects
  • Adverse events were recorded on the last treatment day of each treatment period.
  • During the study, adverse events occurred in 15 patients (60 %) receiving mexiletine and in 9 patients (36 %) receiving placebo.
  • No serious adverse events were observed.
  • One severe AE in the mexiletine arm led to one participant withdrawing from the study.
  • Adverse events of any severity occurring at a frequency of ≥ 10 % whilst on mexiletine treatment included gastrointestinal disorders, infections and parasitic diseases, psychiatric disorders, disorders of the nervous system, and musculoskeletal and connective tissue disorders.
  • However, due to the very minor number of events and the short duration of the MYOMEX study, no reliable conclusions can be drawn regarding the potential for harm.
• Overall assessment
  • For the morbidity endpoint of muscle stiffness, a statistically significant and clinically relevant advantage in favour of mexiletine compared with placebo was observed.
  • In the endpoint category of health-related quality of life, a statistically significant treatment effect in favour of mexiletine over placebo was observed for the ‘symptoms’ domain in each of the subdomains of muscle weakness, muscle paralysis, pain and fatigue.
  • In three of the four sub-domains (muscle spasticity, pain and fatigue), the differences are clinically relevant according to Hedges’ g calculations.
  • In the ‘quality of life’ domain, statistically significant treatment effects in favour of mexiletine compared with placebo were also observed in all subdomains, with the differences in four of the five subdomains (activity, independence, social relationships and emotions) are clinically relevant according to Hedges’ g calculations.
  • In the endpoint category of side effects, no reliable conclusions regarding the potential for harm associated with mexiletin can be drawn from the MYOMEX study due to the very minor number of events and the short duration of the study.
  • Thus, positive and, to a considerable extent, significant effects in favour of mexiletine are evident in terms of improvements in muscle stiffness and health-related quality of life.
  • However, as patients in the present MYOMEX study were treated for a median of only 19 days with mexiletine and 18 days with placebo, the duration of treatment is too short to draw conclusions regarding the sustainability of the effects observed in this study, which had a considerable extent.
  • However, based on the data presented from the MYOMEX study, it is not possible to assess the potential for harm associated with mexiletine due to the short study duration.
  • Overall, therefore, the additional benefit cannot be quantified on the basis of the data presented.

Courtesy translation only, please refer to the German original.