Discussion
RLS, medication-refractory RLS, medication-refractory, daytime sleepiness
SECONDARY
The RESTFUL study, the first large trial to evaluate the efficacy and safety/tolerability of TOMAC for the treatment of medication-refractory RLS, revealed that TOMAC produced significant improvements in RLS symptoms and had excellent safety/tolerability. The CGI-I responder rate (primary endpoint) was almost three-fold higher in the active TOMAC versus sham group. Consistent with clinician ratings of improvement, key secondary endpoints assessed from the participant’s perspective demonstrated that active TOMAC significantly reduced RLS severity, frequency of RLS symptoms, and sleep problems, and improved global symptoms compared with sham. Exploratory analysis indicated that TOMAC reduced trouble falling asleep and daytime sleepiness, common RLS symptoms associated with reductions to quality of life [Participants assigned to active TOMAC continued to improve from Week 4 to Week 8, suggesting a trend toward higher response with longer duration use. Participants originally assigned to sham who switched to active TOMAC experienced significant improvement in RLS symptoms during open-label use. For participants assigned to active TOMAC, AE rates decreased from stage 1 to stage 2, indicating a trend towards increased tolerability with longer use. Adherence remained high through 8 weeks and there was no evidence of habituation. Whereas the study duration of 8 weeks was agreed upon with the US FDA as the appropriate duration to establish safety and efficacy for this patient population, the durability of TOMAC response has now been assessed in a separate extension protocol that followed completers of the RESTFUL study for an additional 24 weeks [In contrast to most clinical trials for commonly prescribed RLS medications, this study exclusively recruited medication-refractory patients and did not require medication washout. These differences in methodology could explain the differences in IRLS responses between these clinical trials. For example, influential clinical trials for pramipexole [Since this study specifically assessed medication-refractory RLS, it does not establish the efficacy of TOMAC for patients who are medication-naïve. Subgroup analysis of a previous study suggested that responses to TOMAC may be similar for medication-naïve and medication-refractory RLS [TOMAC relieves RLS symptoms by engaging similar neuromuscular circuitry as voluntary leg movements such as walking or standing [In summary, TOMAC represents an efficacious and safe treatment option for medication-refractory RLS and is associated with high levels of adherence and patient satisfaction. The safety profile of TOMAC is favorable compared to the recommended medications for RLS [