Effects of Neupro on Cardiovascular Observations in Patients With Restless Legs Syndrome
Condition: Restless Legs Syndrome
MeSH terms: Psychomotor Agitation; Restless Legs Syndrome; Syndrome
Intervention: Rotigotine; Placebo
Intervention description: Rotigotine 1 mg/24 h, 2 mg/24 h, and 3 mg/24 h. Subjects will be titrated to their optimal/maximal dose in weekly increments of 1 mg/24 h during a Titration Period. During Maintenance Period the subjects will continue on their optimal/maximal dose for 28 days. Following the Maintenance Period, subjects will be de-escalated over 7 days, depending on their optimal/maximal dose.; Matching Placebo. Subjects will be titrated to their optimal/maximal dose in weekly increments of 1 mg/24 h during a Titration Period. During Maintenance Period the subjects will continue on their optimal/maximal dose for 28 days. Following the Maintenance Period, subjects will be de-escalated over 7 days, depending on their optimal/maximal dose.
Intervention MeSH terms: Rotigotine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 81.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Rotigotine; Neupro; RLS; Cardiovascular Risk; Nocturnal Blood Pressure

Summary:

      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.
    

Eligibility criteria:

        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)