Real-World Study Supports Peroneal Nerve Stimulation for Restless Legs Syndrome Symptoms

Findings from a 90-day interim analysis from the prospective THRIVE study (NCT06076499), recently published in Sleep, revealed that tonic motor activation (TOMAC; Nidra; Noctrix Health), a FDA-approved wearable peripheral nerve stimulation therapy, produced clinically meaningful reductions in symptom severity among patients with medication-refractory restless leg syndrome (RLS).¹

Among 232 patients meeting criteria for the indicated intent-to-treat population, mean International RLS Study Group (IRLS) scores fell by 8.4 points from baseline to day 90 (95% CI, −7.4 to −9.4), with 79% of patients achieving at least a 3-point reduction, a threshold considered clinically significant.² Investigators reported the therapy was well tolerated, with no serious or severe device-related adverse events (AEs), and noted that nearly one-fifth of patients were able to reduce adjunctive dopamine agonist dosing without loss of symptom control.

Study Overview

Conducted by senior author Jonathan Charlesworth, PhD, co-founder and chief scientific officer at Noctrix Health, and colleagues, THRIVE is a multicenter, prospective, observational, all-comers study evaluating TOMAC in real-world clinical practice. Of 325 enrolled patients, 232 met the FDA indication for moderate-to-severe, refractory RLS and were included in the primary analysis.

Patients self-administered 30-minute stimulation sessions targeting the peroneal nerve as needed. The primary end point was change in IRLS score from baseline to day 90; secondary end points included Clinician Global Impressions-Improvement (CGI-I) score and change in Medical Outcomes Study Sleep Problems Index II (MOS-II) score.

Key Findings

Beyond the primary IRLS reduction, the CGI-I responder rate was 64%, and mean MOS-II score improved by 12.8 points (95% CI, −10.3 to −15.3), indicating better sleep quality. Notably, days per week with RLS symptoms fell from 6.1 to 4.8. Investigators also observed reductions in the proportion of patients meeting thresholds for moderate-to-severe anxiety (27% to 19%) and depression (28% to 18%).

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Overall, reductions in dopamine agonist dosage were more common than increases (18% vs 8%; P = .02), and the 24 patients who lowered their dose, by an average of 52%, maintained that reduction through day 90 without a corresponding worsening in IRLS scores (mean change, −7.6). Device-related AEs occurred in 8% of patients, primarily discomfort and administration-site skin reactions; none were serious, and only 1% of patients discontinued therapy because of AEs.

“Several prior publications demonstrated that TOMAC improved RLS symptoms in randomized controlled trials (RCTs). These new results from THRIVE demonstrate - for the first time - that TOMAC is similarly effective in real-world clinical practice,” Charlesworth told NeurologyLive^®. “This is noteworthy for two reasons.”

“First, RLS improvement with TOMAC was similar regardless of patient characteristics and regardless of adjunctive medications. This differs from gabapentinoid RLS medications, which are less effective in patients with a history of dopaminergic treatment,” Charlesworth added. “These findings could give clinicians more confidence to prescribe TOMAC to patients at various points in the continuum of care, as long as the patient meets the FDA indications for use. For example, TOMAC could be prescribed as an adjunctive to medication as a lower-risk alternative to increasing the dose of dopamine agonist or gabapentinoid medications.”

“Second, this suggests that patients are using the TOMAC device often enough – and correctly enough – to enable robust response to treatment. This is a significant milestone for a device that is patient-administered and where effectiveness depends on correct positioning, intensity, and timing. These results validate the investments that the company commercializing TOMAC - Noctrix Health – has made in orchestrating a network of trained staff to guide patient training and onboarding,” Charlesworth told NeurologyLive.

Clinical Context and Interpretation

Moderate-to-severe RLS affects 2%-3% of adults in the US and Europe and is associated with substantial sleep disruption and daytime impairment.³ Guideline-recommended dopaminergic agents carry risk of augmentation with long-term use, prompting a shift away from first-line dopamine agonist therapy in recent practice guidelines, which instead identify bilateral high-frequency peroneal nerve stimulation as the sole recommended nonpharmacologic option.⁴ TOMAC received FDA marketing authorization based on the randomized, sham-controlled RESTFUL trial (NCT04874155), which reported a comparable 8.7-point IRLS improvement.⁵

The authors noted that THRIVE's less restrictive eligibility criteria, compared with RESTFUL's 12 inclusion and 24 exclusion criteria, did not diminish treatment response, suggesting the therapy's benefit generalizes across a broader, more heterogeneous population than previously studied. No baseline characteristic, including anatomical distribution of symptoms, iron status, or concurrent medication class, predicted differential response after adjusting for baseline severity.

Limitations and Future Research

As an open-label, uncontrolled observational study, THRIVE cannot rule out placebo response, though investigators noted that observed IRLS improvement exceeded the sham response range (3.0-3.8 points) reported in prior randomized trials. Other limitations include lack of objective adherence tracking, self-reported medication changes, and a study population skewing older and predominantly White, which may reflect prescribing and insurance-coverage patterns rather than the broader RLS population. The authors indicated that 1-year outcome data from THRIVE are forthcoming and may help clarify durability of response and the role of treatment adherence.

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REFERENCES
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2. Allen RP. Minimal clinically significant change for the International Restless Legs Syndrome Study Group rating scale in clinical trials is a score of 3. Sleep Med. 2013;14(11):1229. doi:10.1016/j.sleep.2013.08.001
3. Picchietti DL, Van Den Eeden SK, Inoue Y, Berger K. Achievements, challenges, and future perspectives of epidemiologic research in restless legs syndrome (RLS). Sleep Med. 2017;31:3-9. doi:10.1016/j.sleep.2016.06.007
4. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152. doi:10.5664/jcsm.11390
5. Bogan RK, Roy A, Kram J, et al. Efficacy and safety of tonic motor activation (TOMAC) for medication-refractory restless legs syndrome: a randomized clinical trial. Sleep. 2023;46(10):zsad190. doi:10.1093/sleep/zsad190