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A Double-Blind Randomized Controlled Crossover Study to compare the short-efficacy of Burst-SCS with Sham Stimulation, in patients with severe to very severe RLS refractory or intolerant to standard available treatments and/or patients in augmentation, with a two-period-alternating treatment design.
Restless Legs Syndrome (RLS) is a common chronic sleep disorder characterized by an irresistible urge to move the legs, often accompanied by unpleasant sensations that worsens during rest, particularly at night, and improves with movement. Affecting around 5% of the population, moderate to severe RLS can lead to insomnia, involuntary leg movements during sleep (PLMS), depression, and increased cardiovascular risk, significantly impacting sleep and quality of life and typically requiring long-term treatment.
While the exact cause of RLS is unknown, genetic factors, dopamine system alterations, iron deficiency in the brain, and opioid pathways are suspected contributors. It's mainly classified as primary (unknown cause), with secondary RLS linked to other conditions.
Current first-line treatments involve dopamine agonists (DAs) and alpha-2-delta ligands, which are generally effective but can have long-term limitations. A major issue with DAs is "augmentation," a worsening of RLS symptoms that often leads to treatment discontinuation. DAs are also less effective for insomnia, often requiring combination with sedatives. Opioids are effective but are second-line due to side effects and addiction risk. Importantly, while DAs help with sensory symptoms, they often don't significantly improve sleep quality.
Emerging as a promising non-pharmacological approach is electrical neuromodulation, particularly spinal cord stimulation (SCS). Case studies have shown that SCS can improve RLS symptoms, reduce PLMS, and enhance sleep quality, although long-term efficacy has been variable. The potential mechanism of SCS involves activating sensory fibers and inhibitory interneurons in the spinal cord, influencing pain pathways, and modulating brain regions involved in motor control and sleep regulation. This multilevel action may explain the potential benefits of SCS across the sensory, sleep, and motor aspects of RLS.
SCS, typically used for chronic intractable pain, is being investigated as a potential treatment for severe RLS due to overlapping characteristics between the two conditions. RLS has a sensory component that can include pain, and there's evidence suggesting a link between RLS and chronic pain based on high comorbidity, similar sensory processing abnormalities, the effectiveness of certain medications (opioids and α2δ ligands), and a shared hyperexcitable state in the central nervous system. Notably, some patients receiving SCS for chronic pain have also experienced improvement in their RLS symptoms.
This double-blind randomized controlled crossover study aims at comparing the short-efficacy of SCS with Sham Stimulation, in patients with primary or secondary intractable severe or very severe RLS, with a two-period-alternating treatment design. Burst SCS, a specific spinal cord stimulation waveform that delivers pulses in clusters separated by brief periods without stimulation, is chosen over other modalities due to its demonstrated ability to modulate both the sensory and affective components of pain and discomfort. Unlike traditional tonic stimulation, Burst SCS delivers stimulation patterns that more closely resemble natural neuronal firing, and may provide effective symptom relief without inducing paresthesia. Although specific evidence for RLS is still limited, Burst SCS has shown promising results in related neuropathic conditions and is currently considered one of the most advanced and effective neuromodulation techniques available.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment phase: Sham-stimulation | Placebo Comparator | After IPG implantation Burst-SCS is turned on in all participants for 2.5. Then, they will again be double-blind randomized to the 2 treatment orders for 2 weeks per stimulation mode (Sham stimulation or SCS) as fcollows:
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| Treatment phase: SCS-stimulation | Active Comparator | After IPG implantation Burst-SCS is turned on in all participants for 2.5. Then, they will again be double-blind randomized to the 2 treatment orders for 2 weeks per stimulation mode (Sham stimulation or SCS) as fcollows:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Spinal cord stimulation (SCS) | Device | Burst SCS, a specific spinal cord stimulation waveform that delivers pulses in clusters separated by brief periods without stimulation, is chosen over other modalities due to its demonstrated ability to modulate both the sensory and affective components of pain and discomfort. Unlike traditional tonic stimulation, Burst SCS delivers stimulation patterns that more closely resemble natural neuronal firing, and may provide effective symptom relief without inducing paresthesia. |
| Measure | Description | Time Frame |
|---|---|---|
| RLS symptom severity | Change in RLS symptoms and severity as measured by the International RLS-Rating-scale (IRLS-RS) score. The IRLS-RS is a self-administered 10-item questionnaire to assess the severity of sleep disruption and symptoms in RLS patients. It has been validated by the International RLS Study group. Each item is scored from 4 (very severe) to 0 (none). The final score ranges between 0 and 40 and classifies RLS as mild (1-10), moderate (11-20), severe (21-30) and very severe (31-40). A negative change will indicate an improvement in IRLS-RS score and, therefore, in the severity of sleep disruption and symptoms of RLS. | From baseline of the treatment phase to the end of the 2.5 months treatment phase |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment response to SCS in % | The percentage of patients with prolonged response to SCS treatment. A responder is defined as a patient with ≥ 50% reduction (partial responder with ≥ 20%-49% reduction) in the IRLS-RS score. | From baseline of the treatment phase to end of the 2.5 months treatment phase |
| Change in general health quality of life |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Eva Koetsier, PD MD PhD | Contact | +41 (0)91 611 64 82 | eva.koetsier@hin.ch | |
| Mauro Manconi, MD PhD | Contact | +41 (0)91 811 68 25 | mauro.manconi@eoc.ch |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinica Ars Medica | Gravesano | Canton Ticino | 6929 | Switzerland |
IPD will be shared upon resonable request by qualified researchers.
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| ID | Term |
|---|---|
| D012148 | Restless Legs Syndrome |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
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| ID | Term |
|---|---|
| D062187 | Spinal Cord Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D026741 | Physical Therapy Modalities |
| D012046 | Rehabilitation |
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A Double-Blind Randomized Controlled Crossover Study
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| Sham stimulation | Device | For the Sham stimulation condition, the amplitude of the spinal cord stimulation will be set to zero. |
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Change in general health quality of life as measured by the EuroQualityOfLife-5 dimensions (EQ-5D-5L). The EQ-5D-5L questionnaire is a measure of health-related quality of life that includes five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each with five levels of problems (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme), describing 3125 separate health states. The EQ-5D-5L also includes a visual analogue scale (VAS), which records the respondent's self-rated health 'today' on a vertical, visual analogue scale, ranging from 0 "worst imaginable health state" to 100 "best imaginable health state" [26]. A total sum score, ranging from 5 to 25, can also be calculated from the EQ-5D-5L data by summing the levels on the five dimensions, whereby 5 represents the best health state (i.e., no problems in all five dimensions, 11111) and 25 represents the worst health state (i.e., severe problems in all five dimensions, 55555). |
| From baseline of the treatment period to the end of the 2.5 months treatment phase |
| Change in RLS-related quality of life | Change in RLS-related quality of life as measured by the Restless Legs Syndrome Quality of Life Questionnaire (RLSQoL). The RLSQoL is an 18-item self-reported questionnaire that assesses the impact of RLS on daily life, emotional well-being, social life, and work life. Thirteen items are scored on a 5-point scale, the remaining are recorded as either a numerical value or a dichotomous response. Total score range from 0 to 100 with higher scores indicate a better quality of life. A positive change will indicate an improvement in RLSQoL score and, therefore, in the quality of life of RLS patients. | From baseline of the treatment period to the end of the 2.5 months treatment phase |
| Change of Total Sleep Time (TST), Sleep Latency (SL) and Sleep Efficacy (SE) acquired by actigraphy | Change of Total Sleep Time (TST), Sleep Latency (SL) and Sleep Efficacy (SE) acquired by actigraphy with measurements performed prior to the start of the treatment period (from Day -7 to Day -1), in the respective second week of the two weeks of SCS stimulation during the cross-over of the treatment period. The actigraphy is a standard procedure used to measure day-night motor activity and, thus, evaluate circadian rhythms and their disturbances. A small actigraph unit in a wrist-watch-like package is worn on the wrist for a week to measure gross motor activity and, thus, sleep-wake cycles. The movements of the patients are continually recorded. The following objective actigraphy parameters will be evaluated: TST = total amount of sleep time scored during the total recording time. SL = time in minutes from lights off, that marks the patient attempts to sleep, until the first epoch scored as sleep. SE = percentage of total sleep time divided by the time spent in bed | From baseline of the treatment period to the end of the 1 month SCS stimulation during the cross-over of the treatment period |
| Change of PLMS Index recorded by PSG | Change in Periodic limb movements of sleep (PLMS) index from baseline to end of either of the 1 month of stimulation cross-over measured by means of polysomnography recording. The PLMS index is defined as number of PLMS per hour of sleep / total PSG sleep time in minutes. | From baseline of the treatment period to the end of the 1 month SCS stimulation during the cross-over of the treatment period |
| Difference in RLS symptoms and severity between 1 month of SCS vs. Sham stimulation | Difference in RLS symptoms and severity between 1 month of SCS vs. Sham stimulation measured by the IRLS-RS score. The IRLS-RS is a self-administered 10-item questionnaire to assess the severity of sleep disruption and symptoms in RLS patients. It has been validated by the International RLS Study group. Each item is scored from 4 (very severe) to 0 (none). The final score ranges between 0 and 40 and classifies RLS as mild (1-10), moderate (11-20), severe (21-30) and very severe (31-40). A negative change will indicate an improvement in IRLS-RS score and, therefore, in the severity of sleep disruption and symptoms of RLS. | Between 1 month of SCS vs. Sham stimulation |
| Difference in health-related quality of life between 1 month of SCS vs. Sham stimulation | Difference in health-related quality of life between 1 month of SCS vs. Sham stimulation measured by the EQ-5D-5L. The EQ-5D-5L questionnaire is a measure of health-related quality of life that includes five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each with five levels of problems (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme), describing 3125 separate health states. The EQ-5D-5L also includes a visual analogue scale (VAS), which records the respondent's self-rated health 'today' on a vertical, visual analogue scale, ranging from 0 "worst imaginable health state" to 100 "best imaginable health state". A total sum score, ranging from 5 to 25, can also be calculated from the EQ-5D-5L data by summing the levels on the five dimensions, whereby 5 represents the best health state and 25 represents the worst health state. | Between 1 month of SCS vs. Sham stimulation |
| Difference in RLS-related quality of life between 1 month of SCS vs. Sham stimulation | Difference in RLS-related quality of life between 1 month of SCS vs. Sham stimulation measured by the RLSQoL score. The RLSQoL [23, 24] is an 18-item self-reported questionnaire that assesses the impact of RLS on daily life, emotional well-being, social life, and work life. Thirteen items are scored on a 5-point scale, the remaining are recorded as either a numerical value or a dichotomous response. Total score range from 0 to 100 with higher scores indicate a better quality of life. A positive change will indicate an improvement in RLSQoL score and, therefore, in the quality of life of RLS patients. | Between 1 month of SCS vs. Sham stimulation |
| Difference between 1 month of SCS vs. Sham stimulation in TST, SL and SE | Difference between 1month of SCS vs. Sham stimulation in TST, SL and SE acquired by actigraphy. The actigraphy is a standard procedure used to measure day-night motor activity and, thus, evaluate circadian rhythms and their disturbances. A small actigraph unit in a wrist-watch-like package is worn on the wrist for a week to measure gross motor activity and, thus, sleep-wake cycles. The movements of the patients are continually recorded. The following objective actigraphy parameters will be evaluated: TST = total amount of sleep time scored during the total recording time. SL = time in minutes from lights off, that marks the patient attempts to sleep, until the first epoch scored as sleep. SE = percentage of total sleep time divided by the time spent in bed | Between 1 month of SCS vs. Sham stimulation |
| Change of sleep parameters recorded by PSG | Change in PSG-related sleep parameters (Total Sleep Time, Sleep Latency, Sleep Efficacy, Number of awakenings, Arousal index) from baseline to end of either of the 1 month of stimulation cross-over measured by means of polysomnography recording. The following PSG-related sleep parameters will be measured: Total Sleep Time (total amount of sleep time scored during the total recording time); Sleep Latency (time in minutes from lights off, that marks the patient attempts to sleep, until the first epoch scored as sleep); Sleep Efficacy (percentage of total sleep time divided by the time spent in bed); Number of awakenings (the total number of awakenings during the total sleep time); Arousal index (the number of arousals per hour of sleep). | From baselene of the treatment period to the end of the 1 month SCS stimulation during the cross-over of the treatment period. |
| Difference between one month of SCS vs. Sham stimulation in PLMS index, TST, SL, SE, number of awakenings and arousal index | Difference between 1 month of SCS vs. Sham stimulation in PLMS index, TST, SL, SE, number of awakenings and arousal index recorded by PSG. PSG recordings will be carried out in standard sound-attenuated sleep laboratory rooms. The PSG recording may also be performed at home. However, the preparation for the procedure should be carried out at the hospital. Recordings will include electroencephalogram (EEG) (F3, F4, C3, C4, O1, O2 referenced to contralateral mastoid), electroculogram (EOG), electromyogram (EMG) of the submentalis muscle, and EMG of the right and left tibialis anterior muscles. In addition, ECG (CM4 derivation) and sleep respiratory pattern (nasal air flow, thoracic and abdominal respiratory effort, oxygen saturation) will be monitored. Sleep parameters, leg movements, and arousals will be scored according to standardized guidelines. All sleep signals will be stored on hard disk for further analysis. | Between 1 month of SCS vs. Sham stimulation |
| Sleep Center, Neurocenter of Southern Switzerland - EOC | Lugano | Canton Ticino | 6900 | Switzerland |
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| D020447 |
| Parasomnias |
| D001523 | Mental Disorders |