Multi-center, prospective double-blind randomized controlled pivotal study of noninvasive peripheral nerve stimulation (NPNS) with the NTX100 Neuromodulation System for patients with medication-refractory moderate-severe primary RLS

The study consists of a series of two 4-week phases:

Phase 1: Prospective, double-blinded, 1:1 randomized (Active treatment: Sham control)

Phase 2: Prospective, non-randomized, non-blinded, Active treatment

Inclusion Criteria:

1. Subject has received a medical diagnosis of primary restless legs syndrome (RLS).
2. Subject is refractory to RLS medication (as defined in section 7.3).
3. Subject has moderate-severe RLS symptoms as defined by a score of 15 or greater points on IRLS (International Restless Legs Syndrome Study Group Rating Scale [12]) over the week prior to study entry.
4. Subject has RLS symptoms 2 or more nights per week during the week prior to study entry as defined by a score of 2, 3, or 4 on IRLS question #7.
5. RLS symptoms are most significant in the subject's lower legs and/or feet.
6. RLS symptoms are most significant at bedtime, after bedtime, and/or in the 2 hours before bedtime.
7. RLS symptoms between 10am and 6pm are not severe.
8. Subject agrees to not change dosage or schedule of any medications that are known to impact RLS symptoms during the study, including RLS medications, antidepressants, sleep medications, or sedative antihistamines.
9. Subject agrees to not make major lifestyle changes during the study including diet, exercise, career, or other changes that would affect bedtime.
10. 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.
11. Subject is ≥ 22 and ≤ 79 years of age when written informed consent is obtained.
12. Subject has signed a valid, Institutional Review Board (IRB)-approved informed consent form, can understand the requirements of the study and instructions for device usage, and can converse in English

Exclusion Criteria:

1. Subject has RLS that is known to be caused by another diagnosed condition (i.e. secondary RLS).

2. Subject is taking an unstable or inconsistent dose or schedule of medication that is likely to impact RLS symptoms, such as antidepressants, sleep medications, or sedative antihistamines or has changed dosage within the past 30 days.

3. Subject has changed dose and schedule of RLS medications within the month prior to study entry or is otherwise on an inconsistent dose or schedule of RLS medications.

4. Subject reports having significant prior experience with neurostimulation devices (including but not limited to transcutaneous electrical nerve stimulation (TENS) devices) or subject has prior experience with neurostimulation devices developed by the study sponsor.

5. Subject was misdiagnosed with RLS, as determined by the investigator (e.g. actual diagnosis of Periodic Limb Movement Disorder (PLMD), arthritis, leg spasms or neuropathy without comorbid RLS).

6. Subject has a sleep disorder other than RLS that interferes with sleep at the present time (except for obstructive sleep apnea that is stably controlled via Continuous Positive Airway Pressure (CPAP)).

7. Subject has active medical device implant anywhere in the body (including but not limited to pacemakers, spinal cord stimulators, deep brain stimulators) or metal implant in the leg.

8. Subject has failed a nerve conduction study prescribed by a physician or has been diagnosed with severe peripheral neuropathy.

9. Subject reports that bedtime is typically outside of 9pm-3am or reports that bedtime regularly varies by more than 4 hours, such as due to shift work.

10. On nights with no RLS symptoms (if any), subject reports typical sleep onset latency of >60min.

11. Subject has been diagnosed with one of the following conditions:

    • Epilepsy or other seizure disorder
    • Current, active or acute or chronic infection other than common cold
    • A malignancy within the past 5 years (not including basal or squamous cell skin cancer)
    • Stage 4-5 chronic kidney disease or renal failure
    • Severe movement disorder symptoms (Parkinson's disease, Huntington's disease, dyskinesia, dystonia)
    • Deep vein thrombosis
    • Multiple sclerosis

12. Subject has moderate or severe cognitive disorder or mental illness.

13. Subject has current diagnosis of iron-deficient anemia or history of iron-deficient anemia within the past year.

14. Subject has known allergy to device materials, electrode gel, polyurethane foam, or lycra (or severe previous reaction to medical adhesives or bandages).

15. Subject has severe edema affecting lower legs.

16. Subject has any of the following at or near the location of device application.

    • Acute injury
    • Cellulitis
    • Open sores
    • Other skin condition

17. Subject is on dialysis or anticipated to start dialysis while participating in the study.

18. During the NTX100 calibration process, which is identical for subjects in the active and sham arms, subject reports not feeling stimulation sensations up to an intensity of 30mA or finds stimulation intensities less than 15 milliamperes (mA) to be uncomfortable or distracting.

19. Subject has received another investigational device or drug within 30 days before study entry, is planning to receive another investigational device or drug during the study, or is planning to change RLS medications during the study.

20. Subject has undergone a major surgery (excluding dental work) in the 30 days prior to study entry.

21. Subject is unable or unwilling to comply with study requirements.

22. Subject is pregnant or trying to become pregnant.

23. Subject has a medical condition not listed above that may affect validity of the study as determined by the investigator.

24. Subject has a medical condition not listed above that may put the subject at risk as determined by the investigator

Double-blind