Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial

Abstract

Objective: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure.

Methods: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS).

Results: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period.

Interpretation: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency.

Figure 1

Relationship between distal latencies and grip power under cold exposure. Peripheral nerve conduction studies and measurement of grip power were performed at room temperature and under cold exposure (A). The dots and squares represent the distal latencies for each stimulus. The black and blue lines indicate HCs and patients with SBMA, respectively. The differences in distal latencies between room temperature and cold exposure conditions were more prolonged in patients with SBMA than in HCs. The white and blue triangles represent patients with SBMA without and those with cold paresis, respectively. Change of distal latencies between room temperature and cold exposure was calculated from (distal latencies under cold exposure/distal latencies at room temperature) × 100. Prolongation of distal latencies correlated with a decrease in grip power under cold exposure in patients with SBMA (B). SBMA, spinal and bulbar muscular atrophy; HCs, healthy controls.

Figure 2

Flowchart of the clinical trial. Flowchart depicting the MEXPRESS clinical trial enrolment process for patients with spinal and bulbar muscular atrophy.