Tonic Motor Activation (TOMAC) Therapy in Patients With Restless Legs Syndrome and Dopaminergic Augmentation

This study includes a 24-week period during which participants use Tonic Motor Activation (TOMAC) therapy delivered by a noninvasive peroneal nerve stimulation device with investigational settings, including the option for extended-duration stimulation.

Participants are prospectively assigned to receive TOMAC therapy according to a predefined, multi-stage study protocol.

The study consists of two phases: an initial 8-week period of stable medication use with device therapy, followed by a 16-week period during which dopamine agonist medication tapering may occur while device therapy continues, as clinically appropriate.

While statistical power calculations indicate that approximately 15 evaluable participants are sufficient for the primary endpoint, up to 50 participants may be enrolled to improve estimate precision and account for attrition.

Inclusion criteria

• Adult 18 years of age or older when written informed consent is obtained.
• Diagnosis of restless legs syndrome confirmed by IRLSSG criteria.
• Moderate-severe RLS, IRLS ≥15 points at study entry
• Dopaminergic augmentation based on clinician assessment and ASRS (augmentation severity rating scale) ≥5 points at study entry
• Subject agrees to not change the dose or schedule of antidepressants and sleep medications.
• Currently taking stable dose and schedule of dopamine agonist over the 4 weeks prior to enrollment, with average daily dose >= 25mg Levodopa Equivalent Daily Dose (LEDD, https://pdmedcalc.co.uk/calculator).
• Patient reports ≥3 nights per week in the 30d prior to study entry: waking during the sleep period with RLS symptoms that interfered with sleep re-initiation
• RLS sensory symptoms in lower legs and/or feet are equally or more distressing than RLS sensory symptoms in all other anatomical locations.
• The subject possesses the necessary equipment, internet/phone accessibility, and communication ability to complete electronic questionnaires and respond to electronic communications and phone calls from the research staff throughout the in-home portion of the study.
• The subject has signed a valid, IRB-approved informed consent form and can understand the requirements of the study and instructions for device usage.

Exclusion criteria

• Baseline ferritin <75 ng/mL or patient is unwilling to consider iron supplementation.
• IV iron supplementation in the 6 months prior to study entry.
• Change to dose of RLS prescription medication(s) in the 4 weeks prior to study entry.
• Medications that are known to exacerbate RLS symptoms, including: Sedative antihistamines, Tri/tetracyclics, MAOIs, SSRIs and SNRIs, Tramadol, Neuroleptics, Antiemetics, or the anticonvulsants Phenytoin or Methsuximid
• Change in medication that is known to affect RLS symptoms in the 4 weeks prior to study entry (e.g. sleep medication, antihistamines, antidepressants).
• Primary sleep disorder other than RLS that significantly interferes with sleep at the time of screening visit (e.g. obstructive sleep apnea with adherent CPAP usage would not be an exclusion but typical sleep onset latency of >60min on nights without RLS symptoms would be an exclusion).
• Irregular sleep schedule: subject reports that bedtime is typically outside of 21:00 - 03:00 or reports that bedtime regularly varies by more than 4 hours, such as due to shift work.
• Subject has neuropathy and is unable to clearly distinguish between symptoms of neuropathy and symptoms of RLS.
• During the initial investigational device titration process, sensation threshold >= 30mA or distraction threshold < 15mA, or the device does not properly fit the subject.
• One or more of the following confounding comorbidities: Stage 4-5 chronic kidney disease or renal failure , Iron-deficient anemia, Severe cardiac disease (NYHA class IV), Movements disorder other than RLS (Parkinson's disease, Huntington's disease, dyskinesia, dystonia), Multiple Sclerosis , Moderate-severe cognitive disorder (MoCA<26) or mental illness, Moderate-severe edema affecting the lower legs
• One or more of the following contraindications to the investigational device: Diagnosis of epilepsy or other seizure disorder, Metal implant in upper fibula, Known allergy to device materials (or severe previous reaction to medical adhesives or bandages), Open sores, or injury at or near the location of therapy device application.
• Known to be pregnant or trying to become pregnant.
• Medical condition not listed above that may affect validity of the study or put the subject at risk as determined by the investigator.
• Subject is using another investigational device or drug during the study.
• Subject does not understand the study requirements or device instructions, does not have the ability to complete the study assessments, or is unable or unwilling to comply with study requirements.