A Sleep Laboratory Study to Investigate the Safety and Efficacy of the Rotigotine Skin Patch in Subjects With Restless Legs Syndrome and End-Stage Renal Disease Requiring Hemodialysis

Study Overview
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Brief Summary
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This is a sleep laboratory study to evaluate the efficacy and safety of Rotigotine in subjects with Restless Legs Syndrome and End-Stage Renal Disease requiring hemodialysis. The objectives are to demonstrate superiority of Rotigotine against Placebo as well as to investigate the effect of Rotigotine on quality of life and sleep.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group, Polysomnography Study to Investigate Safety and Efficacy of the Rotigotine Transdermal Patch in Subjects With Restless Legs Syndrome and End-Stage Renal Disease Requiring Hemodialysis

Conditions
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Restless Legs Syndrome, End-Stage Renal Disease

Intervention / Treatment
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* Drug: Rotigotine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: End-Stage Renal Disease (ESRD) requiring hemodialysis and regular dialysis schedule Fulfillment of pre-defined criteria of hematology parameters Diagnosis of Restless Legs (RLS) based on the 4 cardinal diagnostic clinical features according to the International Restless Legs Syndrome Study Group Initial response to previous dopaminergic treatment for RLS, or has had no previous dopaminergic treatment (ie, de novo) Score of ≥ 15 points on the IRLS (indicating moderate to severe RLS) at Baseline Score of ≥ 11 points on the RLS-DI (Diagnostic Index) at Baseline Score of ≥ 4 points on the Clinical Global Impressions (CGI) Item 1 assessment (indicating moderately ill) at Baseline Scores ≥ 15 Periodic Limb Movements (PLMs) per hour on the Periodic Limb Movement Index (PLMI) based on Polysomnography (PSG) (recorded during the second night) as assessed by the investigator at Baseline Exclusion Criteria: Clinically relevant Polyneuropathy or Varicosis which cannot be clearly differentiated from RLS symptoms in the opinion of the investigator Clinically relevant concomitant diseases, such as Attention Deficit Hyperactivity Disorder, Painful Legs, and Moving Toes Other central nervous system diseases Evidence of an impulse control disorder according to the modified Minnesota Impulsive Disorders Interview (mMIDI) Lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ('yes') to either Question 4 or Question 5 of the Columbia-Suicidality Severity Rating Scale (C-SSRS) at Screening (Visit 1) or Baseline (Visit 2) Prior history of psychotic episodes History of symptomatic (not asymptomatic) Orthostatic Hypotension Clinically relevant Cardiovascular Disease Clinically relevant Venous or Arterial Peripheral Vascular Disease Malignant Neoplastic Disease requiring therapy within 12 months prior to Screening (Visit 1) Treatment with any of the following drug classes: neuroleptics, norepinephrine and dopamine reuptake inhibitors (bupropion), gabapentin, budipine, dopamine antagonist antiemetics (except domperidone), opioids, monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or psychostimulants (eg, amphetamines) Subject is pregnant, nursing, or is a woman of childbearing potential who is not surgically sterile, 2 years postmenopausal, or does not consistently use 2 combined effective methods of contraception (including at least 1 barrier method), unless sexually abstinent Previous treatment with dopamine agonists within a period of 14 days prior to Baseline (Visit 2), or L-dopa within 7 days prior to Baseline (Visit 2) Medical history indicating intolerability to dopaminergic therapy (if pretreated) or has experienced Augmentation (Garcia-Borreguero and Williams, 2010) when previously treated with any dopaminergic agent Subject has received previous treatment with Rotigotine Known hypersensitivity to any of the components of the study medication, such as a history of significant Skin Hypersensitivity to adhesives, known Hypersensitivity to other transdermal medications, or unresolved Contact Dermatitis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rotigotine<br>Rotigotine Transdermal Patch 1 mg/24 h, 2 mg/24 h or 3 mg/24 h once daily depending on optimal dose; maximal dose is 3 mg/24 h. | Drug: Rotigotine<br>* Transdermal patch; Dose: 1 mg/24 h, 2 mg/24 h or 3 mg/24 h once daily depending on optimal dose; maximal dose is 3 mg/24 h. Subjects start with a Rotigotine dose of 1 mg/24 h for 1 week. The dose can be increased weekly during Up-Titration Period until either the optimal or the maximal dose of 3 mg/24 h has been reached. Subjects will maintain the optimal/maximal dose during the 2-week Maintenance Period. Following the Maintenance Period, subjects will be de-escalated from their optimal dose by decreasing the dose by 1 mg/24 h every other day during Taper Period until complete withdrawal.<br>* Other names: Neupro;|
| Placebo Comparator: Placebo<br>Transdermal patch matched according to patch size and appearance. | Drug: Placebo<br>* Transdermal patch; Patches matching to active treatment patches in size and appearance. Up to 3 weeks of Titration, 2 weeks of Maintenance, Up to 4 days of Taper Period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio From Baseline to the End of the 2-week Maintenance Period in Periodic Limb Movement Index (PLMI) | The PLMI is defined as Periodic Limb Movements (PLMs)/ total time in bed in hours. PLMs are measured by Polysomnography (PSG). The reduction of the PLMI is reflected in terms of the ratio from Baseline to the end of the Maintenance Period and was calculated as [PLMI at end of Maintenance Period (MP)] / [PLMI at Baseline]. A PLMI Ratio <1 indicates an improvement from Baseline to the end of the 2-week MP. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Periodic Limb Movements Index (PLMI) to the End of the Maintenance Period | The PLMI is defined as Periodic Limb Movements (PLMs)/ total time in bed in hours. PLMs are measured by Polysomnography (PSG). A negative value in change from Baseline indicates an improvement from Baseline to the end of the Maintenance Period. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the International Restless Legs Syndrome Study Group Rating Scale (IRLS) Sum Score to the End of the Maintenance Period | The IRLS is a subject based scale that consists of 10 items to evaluate the severity of major RLS symptoms and the impact of the disease on subjects' functioning in daytime activities. Each of the 10 items is measured on a scale that ranges from 0 (not present) to 4 (severe). A sum score between 0 (no RLS symptoms present at all) and 40 (maximum severity in all symptoms) across all 10 items will be calculated. A negative value in Change from Baseline indicates an improvement from Baseline in IRLS. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in Clinical Global Impressions (CGI) Item 1 Score | The CGI Item 1 score measures the severity of illness on a scale that ranges from 0 (Not assessed) to 7 (Among the most extremely ill). | Visit 2 (Baseline); Visit 6 (End of Maintence Period) | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 1 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 1 measures satisfaction with sleep during the last seven nights on an 11-point scale that ranges between 0 (completely satisfied) to 10 (completely dissatisfied). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 2 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 2 measures the severity of RLS symptoms during the last 7 nights in the situation of falling asleep. This is measured on an 11-point scale that ranges between 0 (none) to 10 (very severe). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 3 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 3 measures the severity of RLS symptoms during the last seven nights on an 11-point scale that ranges between 0 (none) to 10 (very severe). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 4 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 4 measures the severity of RLS symptoms during the last seven days at rest on an 11-point scale that ranges between 0 (none) to 10 (very severe). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 5 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 5 measures the severity of RLS symptoms during the last seven days engaged in activities on an 11-point scale that ranges between 0 (none) to 10 (very severe). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-6 (RLS-6) Rating Scale 6 to the End of the Maintenance Period | The RLS-6 consists of six scales of which four scales are designed to assess severity of RLS and two scales cover sleep and daytime tiredness. Scale 6 measures the severity of daytime tiredness/ sleepiness on an 11-point scale that ranges between 0 (not at all) to 10 (very severe). The ratings are given by the subjects. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Periodic Limb Movement During Sleep Arousal Index (PLMSAI) to the End of the Maintenance Period | The Periodic Limb Movement during Sleep Arousal Index (PLMSAI) reflects the influence of the PLM on subject's sleep. Arousal is defined as sudden change in the Electroencephalogram (EEG) activity and the index illustrates to what degree the PLMs contribute to arousal from sleep. A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in Sleep Efficiency to the End of the Maintenance Period | Sleep stages and time spent in each sleep stage are determined from Electroencephalogram (EEG) readings. Sleep stage data will be used to calculate sleep efficiency. Sleep efficiency will be presented as percentages. Sleep efficiency is the percentage of time in bed spent asleep. A postive value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Restless Legs-Quality of Life (RLS-QoL) Total Score to the End of the Maintenance Period | The RLS-QoL is a disease-specific questionnaire to evaluate quality of life. It consists of 12 items. A total score will be calculated from all of the 12 items. The overall sum score can be from 0 (highest QoL) to 60 (lowest QoL). A negative value in Change from Baseline indicates an improvement from Baseline. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Short-Form-36 (SF-36) Item Questionnaire Mental Component Summary (MCS) to the End of the Maintenance Period | The SF-36 is a 36 item generic human research quality of life instrument that uses a recall period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), Role Physical (4 items), Bodily Pain (2 items), General Health (5 items), Vitality (4 items), Social Functioning (2 items), Role Emotional (3 items), Mental Health (5 items), and a further unscaled single item (question 2) for perceived stability or change in health (Health Transition) during the last year. The norm based scores (based on the US general population) were used for analysis. For the MCS, the lowest and highest possible scores are -9 and 82 (rounded). The SF-36 domains (subscores) are scored so that a higher score indicates a better health state. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 
| Change From Baseline in the Short-Form-36 (SF-36) Item Questionnaire Physical Component Summary (PCS) to the End of the Maintenance Period | The SF-36 is a 36 item generic human research quality of life instrument that uses a recall period of 4 weeks. Items are grouped into 8 domains as follows: Physical Functioning (10 items), Role Physical (4 items), Bodily Pain (2 items), General Health (5 items), Vitality (4 items), Social Functioning (2 items), Role Emotional (3 items), Mental Health (5 items), and a further unscaled single item (question 2) for perceived stability or change in health (Health Transition) during the last year. The norm-based scores (based on the US general population) were used for analysis. For the PCS, the lowest and highest possible scores are 1 and 81 (rounded). The SF-36 domains (subscores) are scored so that a higher score indicates a better health state. | From Baseline over the Up-Titration Period (up to 3 Weeks) to the end of the 2-Week Maintenance Period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotigotine, Neupro, Restless Legs Syndrome, RLS, End-Stage Renal Disease