Outcomes and statistical analysis
RLS
Data analyses, which were primarily descriptive, were performed using Microsoft Excel.The primary endpoint was the percentage of participants who completed step-down 1 with a CGI-I score of ≤ 5 and actual opioid dose reduction of ≥ 20%, in which both CGI-I and opioid dose reduction were assessed during step-down 1 assessment period relative to baseline (week prior to study entry). The primary endpoint and a success criterion of 50% were prespecified in the protocol prior to enrollment of the first subject. The CGI-I is a 7-point clinician-rated scale [Maximum well-tolerated opioid reduction for each participant was defined as the largest reduction in opioid dose with a CGI-I score ≤ 5 in which both CGI-I and opioid dose reduction were assessed during assessment periods relative to baseline.Participants who discontinued prior to step-down 1 completion for any reason were considered failures for the primary endpoint and those who discontinued prior to step-down 1 completion or had a CGI-I > 5 were counted as having 0% maximum well-tolerated opioid reduction. Other than these instances, there were no missing data. For all participants who successfully completed a step-down with a CGI-I score of ≤ 5, descriptive statistics were calculated for the CGI-I score and for change to the IRLS total score relative to baseline.Post hoc sensitivity analysis evaluated the impact of replacing the CGI-I success criterion with an IRLS-based success criterion. For this analysis, all other statistical treatment was the same as described above for the primary endpoint.The Pearson correlation coefficient was used to evaluate the relationships between-participant variation in maximum well-tolerated opioid reduction and the following variables: baseline opioid dose (MME), baseline IRLS total score, participant-rated RLS symptom relief during 30-min TOMAC sessions, and participant-rated RLS symptom relief during the 30-min immediately following TOMAC sessions. The latter two factors were assessed at the end of each step-down, and thus analysis of those factors excluded participants who withdrew during step-down 1 for reasons unrelated to RLS symptoms. Participant-rated RLS symptom relief was evaluated using the Patient Global Impressions of Improvement scale (PGI-I; analogous to CGI-I above) [Safety outcome measures were centrally assessed. The count and proportion of participants reporting AEs with new onset or worsening (relative to baseline) were assessed. AEs were coded and summarized at the participant level by Medical Dictionary for Regulatory Activities System Organ Class and Preferred Terms and by seriousness, severity, and relationship to the device.Objective exposure to therapy was assessed during assessment periods through analysis of therapy unit device logs, which recorded the timing of each completed 30-min therapy session. Device logs were available for 14 of the 15 participants who successfully reduced opioid dose. Partial sessions with < 30-min duration were not included in analysis. Participants were instructed to use the device only on days with RLS symptoms and thus adherence was assessed by comparing frequency of completed sessions (from device logs) to frequency of participant reported RLS symptoms derived from an electronic daily questionnaire developed for this study (See Additional File 