Rotigotine Effect on All-day Functioning and Quality of Life in Subjects With Moderate to Severe Restless Legs Syndrome (RLS)

A Phase 3B, Double-Blind, Randomized, Placebo-Controlled Study of Rotigotine and Its Effect on All-Day Functioning and Quality of Life in Subjects With Moderate to Severe Idiopathic Restless Legs Syndrome

The purpose of the study is to show that Rotigotine improves Restless Legs Syndrome (RLS) symptoms in subjects with moderate to severe RLS during both day and evening.

Inclusion Criteria:

• An Institutional Review Board (IRB)-approved written Informed Consent Form (ICF) is signed and dated by the subject
• 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 male or female, and is ≥ 18 and ≤ 75 years of age
• Subject is able to apply/remove the study patch correctly
• Subject meets the diagnosis of Idiopathic Restless Legs Syndrome (IRLS) 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 the 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 down 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)
• At Baseline (Visit 2), subject has a score of ≥ 11 on the RLS-Diagnostic Index (RLS-DI) (Benes and Kohnen, 2009)
• Subject must attempt all 4 Suggested Immobilization Test (SIT) assessments at Baseline (Visit 2)
• At Baseline (Visit 2) subject has an average Multiple Suggested Immobilization Test Discomfort Scale (m-SIT-DS) of at least 1.5 over the course of the Multiple Suggested Immobilization Test (m SIT)
• The subject's Body Mass Index is ≥ 18 kg/m^2 and ≤ 35 kg/m^2 at Visit 1
• At Baseline (Visit 2), subject has a score of ≥ 15 on the International Restless Legs Scale (IRLS) (indicating moderate to severe RLS)
• At Baseline (Visit 2), subject has a score of "Severe" or "Very Severe" on Item 8 of the IRLS (Item 8: When you had RLS symptoms how severe were they on average?)
• At Baseline (Visit 2), subject has a score of ≥ 4 points on the Clinical Global Impression (CGI) Item 1 assessment (indicating moderately ill)

Exclusion Criteria:

• Subject has previously participated in this study or has received previous treatment with Rotigotine
• Subject has participated in another study of an investigational medicinal product (IMP) or a medical device within the last 30 days prior to Visit 1, or is currently participating in another study of an IMP or a medical device
• Subject has secondary RLS (eg, due to Renal Insufficiency [Uremia], Iron Deficiency Anemia or Rheumatoid Arthritis)
• Subject has had a Ferritin value of ≤ 18 µg/L within the last 3 months prior to Baseline (Visit 2)
• Subject has RLS associated with previous or concomitant therapy with Dopamine 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 evidence of an Impulse Control Disorder according to the Modified Minnesota Impulsive Disorders Interview (mMIDI) at Screening (Visit 1)
• 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 Polysomnography (PSG) (local PSG evaluations) or evidenced by subject history
• 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)
• 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, 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 last 12 months prior to Visit 1
• Subject has any medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the subject's well being or ability to participate in this study
• Subject has a 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 medically acceptable 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 (Visit 1) or Baseline Visit (Visit 2), subject has Symptomatic Orthostatic Hypotension with a decrease of Blood Pressure (BP) from supine to standing position of ≥ 20 mmHg in systolic BP or of ≥ 10 mmHg in diastolic BP taken from the 5-minute supine and 1- and/or 3-minute standing measurements at Visit 1 or Visit 2
• Subject is treated with Dopamine Agonists within a period of 7 days prior to Baseline (Visit 2) or L-Dopa within 3 days prior to Baseline (Visit 2)
• Subject has a known history indicating intolerability to prior Dopaminergic therapy (if pretreated) when previously treated with any Dopaminergic agent
• Subject has a known hypersensitivity to any 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