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Non-dystrophic myotonias are genetic conditions that cause significant morbidity and impairment of quality life in a young cohort. Sodium channel blockers are used for symptomatic relief. We performed a phase III, randomised, double-blinded, cross-over, non-inferiority trial to compare lamotrigine and mexiletine head-to-head. Participants had genetically confirmed symptomatic Non-dystrophic myotonia. Participants were randomised to receive either mexiletine for 8 weeks followed by lamotrigine for 8 weeks, or lamotrigine followed by mexiletine with appropriate washout. The primary outcome measure was the interactive voice response diary (IVR-diary) stiffness score (0-9 scale) and non-inferiority was assessed with a predefined margin of 0.5. Sixty participants were enrolled. We were not able to show that lamotrigine was non-inferior to mexiletine. The mean mexiletine-lamotrigine difference in IVR-diary stiffness score was -0.09 (95% CI -0.58 to 0.39). However, improvements from baseline in stiffness scores and all secondary outcome measures were comparable between mexiletine and lamotrigine - the mean IVR stiffness score reduced from 5.3 at baseline, to 2.52 with mexiletine and 2.62 with lamotrigine. The most common adverse event was indigestion/reflux with both treatments. No serious adverse events were seen. Importantly, improvements in all outcome measures from baseline were comparable between lamotrigine and mexiletine. As such, lamotrigine is a key consideration in the treatment algorithm of Non-dystrophic myotonias. We discuss a treatment approach considering the trial results, local economics, patient needs and pharmacokinetics.v.vivekanandam@ucl.ac.uk