Restless Legs Syndrome
Conditions
Brief summary
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
Detailed description
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
Interventions
Noninvasive peripheral nerve stimulation device programmed to active mode.
Noninvasive peripheral nerve stimulation device programmed to sham mode.
DEVICENTX100 Neuromodulation System - Open-Label
Noninvasive peripheral nerve stimulation device programmed to active mode.
Sponsors
Noctrix Health, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Study consists of two phases. Phase 1: Randomized 1:1 between Active treatment and Sham control Phase 2: Non-randomized, Active treatment
Eligibility
Sex/Gender
ALL
Age
22 Years to 79 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects for Which the Clinician Reported Much Improved or Very Much Improved on the Clinical Global Impressions-Improvement (CGI-I) Scale for TOMAC Compared to Sham | Week 4 | Responder rate is defined as the proportion of responses of Much Improved or Very Much Improved relative to baseline on the investigator-rated 7-point CGI-I scale. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score | Week 4 | IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe. |
| Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index II (MOS-II) Score | Week 4 | MOS-II is a subscale of the participant-rated MOS questionnaire that measures subjective sleep quality. The MOS-I (6-items) and MOS-II (9-items) are the two validated subscales of the 12-item MOS Sleep Scale. Both are scored from 0 to 100, where 100 corresponds to the worst possible sleep problems and 0 corresponds to no sleep problems. See https://labs.dgsom.ucla.edu/hays/files/view/docs/surveys/sleep/sleepman-112603.pdf for more information. |
| Responder Rate on Patient Global Impressions-Improvement (PGI-I) Scale | Week 4 | Responder rate is defined as the proportion of responses of Much Improved or Very Much Improved relative to baseline on the participant-rated 7-point PGI-I scale. |
| Mean Clinical Global Impressions-Improvement (CGI-I) Scale Rating | Week 4 | Mean rating on the investigator-rated 7-point Likert CGI-I scale, where lower scores indicate improvement. Possible choices (followed by scale value) are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very Much Worse (7). |
| Score for Question #7 of the International Restless Legs Syndrome Study Group Rating Scale (IRLS) | Week 8 | Question #7 of the IRLS assesses the participant-rated frequency (days/week) of RLS symptoms on a scale from 0 to 4, where lower scores indicate less frequent symptoms |
| Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index I (MOS-I) Score | Week 4 | MOS-I is a subscale of the participant-rated MOS questionnaire that measures subjective sleep quality. The MOS-I (6-items) and MOS-II (9-items) are the two validated subscales of the 12-item MOS Sleep Scale. Both are scored from 0 to 100, where 100 corresponds to the worst possible sleep problems and 0 corresponds to no sleep problems. See https://labs.dgsom.ucla.edu/hays/files/view/docs/surveys/sleep/sleepman-112603.pdf for more information. |
Countries
United States
Participant flow
Recruitment details
Subjects must have received a medical diagnosis of primary restless legs syndrome (RLS), have moderate-severe RLS and be refractory to RLS medication.
Participants by arm
| Arm | Count |
|---|---|
| TOMAC Group Noninvasive peripheral nerve stimulation device programmed to deliver active stimulation - Phase 1
NTX100 Neuromodulation System - Active: Noninvasive peripheral nerve stimulation device programmed to active mode. | 68 |
| Sham Control Group Noninvasive peripheral nerve stimulation device programmed to deliver non-therapeutic (sham) stimulation - Phase 1
NTX100 Neuromodulation System - Sham: Noninvasive peripheral nerve stimulation device programmed to sham mode. | 65 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | TOMAC Group | Sham Control Group | Total |
|---|---|---|---|
| Age, Customized | 56.3 years STANDARD_DEVIATION 10.96 | 58.6 years STANDARD_DEVIATION 11.81 | 57.46 years STANDARD_DEVIATION 11.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 4 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 61 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| IRLS Total Score at Baseline | 25.2 Units on a scale STANDARD_DEVIATION 5.3 | 25.4 Units on a scale STANDARD_DEVIATION 5.3 | 25.3 Units on a scale STANDARD_DEVIATION 5.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 64 Participants | 65 Participants | 129 Participants |
| Sex: Female, Male Female | 39 Participants | 41 Participants | 80 Participants |
| Sex: Female, Male Male | 29 Participants | 24 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 65 |
| other Total, other adverse events | 28 / 68 | 23 / 65 |
| serious Total, serious adverse events | 0 / 68 | 0 / 65 |
Outcome results
Primary
Number of Subjects for Which the Clinician Reported Much Improved or Very Much Improved on the Clinical Global Impressions-Improvement (CGI-I) Scale for TOMAC Compared to Sham
Responder rate is defined as the proportion of responses of Much Improved or Very Much Improved relative to baseline on the investigator-rated 7-point CGI-I scale.
Time frame: Week 4
Population: Primary Efficacy Endpoint (CGI-I Responder Rate at Week 4) - (ITT Population)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TOMAC Group | Number of Subjects for Which the Clinician Reported Much Improved or Very Much Improved on the Clinical Global Impressions-Improvement (CGI-I) Scale for TOMAC Compared to Sham | 29 Participants |
| Sham Control Group | Number of Subjects for Which the Clinician Reported Much Improved or Very Much Improved on the Clinical Global Impressions-Improvement (CGI-I) Scale for TOMAC Compared to Sham | 10 Participants |
Secondary
Mean Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score
IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe.
Time frame: Week 4
Population: Key Secondary Efficacy Endpoints (ITT Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TOMAC Group | Mean Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score | -7.2 score on a scale | Standard Deviation 6.2 |
| Sham Control Group | Mean Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score | -3.8 score on a scale | Standard Deviation 5.9 |
Secondary
Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index II (MOS-II) Score
MOS-II is a subscale of the participant-rated MOS questionnaire that measures subjective sleep quality. The MOS-I (6-items) and MOS-II (9-items) are the two validated subscales of the 12-item MOS Sleep Scale. Both are scored from 0 to 100, where 100 corresponds to the worst possible sleep problems and 0 corresponds to no sleep problems. See https://labs.dgsom.ucla.edu/hays/files/view/docs/surveys/sleep/sleepman-112603.pdf for more information.
Time frame: Week 4
Population: Key Secondary Efficacy Endpoints (ITT Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TOMAC Group | Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index II (MOS-II) Score | -13.7 score on a scale | Standard Deviation 14.9 |
| Sham Control Group | Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index II (MOS-II) Score | -4.0 score on a scale | Standard Deviation 14.8 |
Secondary
Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index I (MOS-I) Score
MOS-I is a subscale of the participant-rated MOS questionnaire that measures subjective sleep quality. The MOS-I (6-items) and MOS-II (9-items) are the two validated subscales of the 12-item MOS Sleep Scale. Both are scored from 0 to 100, where 100 corresponds to the worst possible sleep problems and 0 corresponds to no sleep problems. See https://labs.dgsom.ucla.edu/hays/files/view/docs/surveys/sleep/sleepman-112603.pdf for more information.
Time frame: Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TOMAC Group | Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index I (MOS-I) Score | -11.8 score on a scale | Standard Deviation 14.7 |
| Sham Control Group | Mean Change From Baseline in Medical Outcomes Study Sleep Problems Index I (MOS-I) Score | -2.8 score on a scale | Standard Deviation 14.9 |
Secondary
Mean Clinical Global Impressions-Improvement (CGI-I) Scale Rating
Mean rating on the investigator-rated 7-point Likert CGI-I scale, where lower scores indicate improvement. Possible choices (followed by scale value) are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very Much Worse (7).
Time frame: Week 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TOMAC Group | Mean Clinical Global Impressions-Improvement (CGI-I) Scale Rating | 2.6 score on a scale | Standard Deviation 1.1 |
| Sham Control Group | Mean Clinical Global Impressions-Improvement (CGI-I) Scale Rating | 3.5 score on a scale | Standard Deviation 0.9 |
Secondary
Responder Rate on Patient Global Impressions-Improvement (PGI-I) Scale
Responder rate is defined as the proportion of responses of Much Improved or Very Much Improved relative to baseline on the participant-rated 7-point PGI-I scale.
Time frame: Week 4
Population: Key Secondary Efficacy Endpoints (ITT Population)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TOMAC Group | Responder Rate on Patient Global Impressions-Improvement (PGI-I) Scale | 33 Participants |
| Sham Control Group | Responder Rate on Patient Global Impressions-Improvement (PGI-I) Scale | 12 Participants |
Secondary
Score for Question #7 of the International Restless Legs Syndrome Study Group Rating Scale (IRLS)
Question #7 of the IRLS assesses the participant-rated frequency (days/week) of RLS symptoms on a scale from 0 to 4, where lower scores indicate less frequent symptoms
Time frame: Week 8
Population: Key Secondary Efficacy Endpoints (ITT Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TOMAC Group | Score for Question #7 of the International Restless Legs Syndrome Study Group Rating Scale (IRLS) | -0.9 Days per Week | Standard Deviation 1.07 |
| Sham Control Group | Score for Question #7 of the International Restless Legs Syndrome Study Group Rating Scale (IRLS) | -0.6 Days per Week | Standard Deviation 1.2 |