Effects of Neupro on Cardiovascular Observations in Patients With Restless Legs Syndrome

Multicenter, Double-Blind, Placebo-Controlled, Two-Arm, Randomized, Parallel, Treatment Intervention, Sleep Lab Phase 4 Study to Assess the Effect of Rotigotine on Nocturnal Blood Pressure in Patients With Idiopathic Restless Legs Syndrome

Periodic Limb Movements (PLMs) during sleep in patients with Restless Legs Syndrome (RLS) have been shown to be associated with elevations in Blood Pressure (BP). Rotigotine has been shown to effectively reduce the incidence of PLMs in patients with RLS. The current study aims to demonstrate that treatment with Rotigotine could help reduce the number of nocturnal BP elevations associated with PLMs in patients with RLS.

Inclusion Criteria:

• Subject is informed and given ample time and opportunity to think about her/his participation and give her/his written informed consent
• Subject understands the investigational nature of the study and is willing and able to comply with the study requirements. Subject is willing to accept that he/she might be treated with placebo during the Treatment Period
• Subject is able to apply/remove the study patch correctly
• Subject is male or female, and is ≥18 and ≤75 years of age
• Subject meets the diagnosis of idiopathic Restless Legs Syndrome (RLS) based on the 4 essential clinical features according to the International Restless Legs Syndrome Study Group (Allen et al,2003): 1. An urge to move legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (The urge to move can be present without uncomfortable sensations. Arms or other body parts can also be affected) 2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting 3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues 4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night (When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present)
• Subject has a score of ≥11 on the RLS-Diagnostic Index (RLS-DI) (Benes and Kohnen, 2009)
• Subject has an initial response to previous dopaminergic treatment for RLS or has no previous dopaminergic treatment (ie, de novo)
• The subject's Body Mass Index (BMI) is ≥18 kg/m^2 and ≤35 kg/m^2
• At Baseline subject has a score of ≥15 on the IRLS (indicating moderate to severe RLS)
• At Baseline subject has a score of ≥4 points on the CGI Item 1 assessment (indicating moderately ill)
• At Baseline subject has a score of ≥15 PLM/h on the Periodic Limb Movements Index (PLMI) based on polysomnography (PSG) (recorded during the second night) as assessed by the investigator
• Subjects are on a concomitant dose of antihypertensives that is at a stable dose for at least 4 weeks prior to Baseline and hypertension is reasonably controlled while the subject agrees to continue at this dose for the duration of the study, or subject has not received concomitant treatment with antihypertensives for at least 4 weeks prior to Baseline and does not intend to start such use during the study

Exclusion Criteria:

• Subject has RLS due to renal insufficiency (uremia), iron deficiency anemia, or rheumatoid arthritis
• Subject has RLS associated with previous or concomitant therapy with dopamine D2 receptor antagonists, butyrophenones, metoclopramide, atypical antipsychotics (eg, olanzapine), tri- and tetra-cyclic antidepressants, mianserine, or lithium or H2-blockers (eg, cimetidine), or due to withdrawal from drugs such as anticonvulsants, benzodiazepines, barbiturates, and other hypnotics
• Subject has a history of sleep disturbances, such as sleep apnea syndrome (including obstructive sleep apnea), narcolepsy, sleep attacks/sudden onset of sleep, or myoclonus epilepsy either observed during PSG (local PSG evaluations) or evidenced by subject history
• Subject has uncontrolled hypertension according to the judgment of the investigator
• Subject has additional clinically relevant concomitant diseases, such as attention deficit hyperactivity disorder, polyneuropathy, akathisia, claudication, varicosis, muscle fasciculation, painful legs and moving toes, or radiculopathy
• Subject has other central nervous system diseases, such as Parkinson's disease, dementia, progressive supranuclear paresis, multisystem atrophy, Huntington's chorea, amyotrophic lateral sclerosis, or Alzheimer's disease.
• Subject has a prior history of psychotic episodes
• Subject has a history of chronic alcohol or drug abuse within the previous 12 months
• Subject has any medical or psychiatric condition, which in the opinion of the investigator, can jeopardize or would compromise the subject's ability to participate in this study
• Subject has clinically relevant cardiac dysfunction and/or arrhythmias (eg, suspected conduction system dysregulations, second or third degree atrioventricular block, complete left or right bundle branch block, sick sinus syndrome, New York Heart Association Class III or IV congestive heart failure, or had a myocardial infarction within 12 months prior to Screening [Visit 1])
• Subject has clinically relevant venous or arterial peripheral vascular disease
• Subject has a malignant neoplastic disease requiring therapy within 12 months prior to Screening (Visit 1)
• Subject is currently receiving treatment with any of the following drug classes: neuroleptics, hypnotics, antidepressants, anxiolytic drugs, anticonvulsive therapy, budipine, dopamine antagonist antiemetics (except domperidone), opioids, benzodiazepines, monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, sedative antihistamines, psychostimulates, or amphetamines. If subject has received such therapy, a Washout Period of at least 7 days prior to Baseline (Visit 2) is required before starting treatment in this study
• 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
• Subject is a shift worker or performs other continuous non-disease-related life conditions which do not allow regular sleep at night
• At Screening Visit or Baseline Visit subject has symptomatic orthostatic hypotension
• Subject is treated with dopamine agonists within a period of 14 days prior to Baseline or L-dopa within 7 days prior to Baseline
• Subject has a medical history indicating intolerability to prior dopaminergic therapy (if pretreated)
• Subject has received previous treatment with Rotigotine
• Subject has participated in another study of an investigational drug or device within the 28 days prior to Visit 2 (Baseline) or is currently participating in another study of an investigational drug
• Subject has a 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 has unresolved contact dermatitis
• Subject has a 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-Suicide Severity Rating Scale (C-SSRS) at Screening (Visit 1)