Dose Escalating Study of Rotigotine in Pediatric Subjects With Restless Legs Syndrome

• Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Apparent total body clearance (Cl/f) of unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2).
• Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Apparent total body clearance (Cl/f) of unconjugated Rotigotine 1 mg/24 h (5 cm^2).
• Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Apparent total body clearance (Cl/f) of unconjugated Rotigotine 2 mg/24 h (10 cm^2).
• Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Apparent total body clearance (Cl/f) of unconjugated Rotigotine 3 mg/24 h (15 cm^2).
• Volume of Distribution (Vd) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Volume of distribution (Vd) of unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2).
• Volume of Distribution (Vd) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Volume of distribution (Vd) of unconjugated Rotigotine 1 mg/24 h (5 cm^2).
• Volume of Distribution (Vd) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Volume of distribution (Vd) of unconjugated Rotigotine 2 mg/24 h (10 cm^2).
• Volume of Distribution (Vd) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2) [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  Volume of distribution (Vd) of unconjugated Rotigotine 3 mg/24 h (15 cm^2).

• Area Under the Curve (AUCss) of unconjugated rotigotine 0.2 mg /24 h (1 cm^2). [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  AUCss at steady state for rotigotine patch 0.2 mg/24 h (1 cm^2).
• Area Under the Curve (AUCss) of unconjugated rotigotine 0.5 mg/24 h (2.5 cm^2). [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  AUCss at steady state for rotigotine patch 0.5 mg/24 h (2.5 cm^2).
• Area Under the Curve (AUCss) of unconjugated rotigotine 1 mg/24 h (5 cm^2). [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  AUCss at steady state for rotigotine patch 1 mg/24 h (5 cm^2).
• Area Under the Curve (AUCss) of unconjugated rotigotine 2 mg/24 h (10 cm^2). [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  AUCss at steady state for rotigotine patch 2 mg/24 h (10 cm^2).
• Area Under the Curve (AUCss) of unconjugated rotigotine 3 mg/24 h (15 cm^2). [ Time Frame: 0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on last day per dose step ] [ Designated as safety issue: No ]
  AUCss at steady state for rotigotine patch 3 mg/24 h (15 cm^2).

This will be a multicenter, open-label, dose-escalation, Phase 2A study with multiple monotherapy administration of the Rotigotine transdermal system. The study will be conducted in adolescent subjects (13 to <18 years of age) with idiopathic Restless Legs Syndrome (RLS).

Study design was changed and an amendment was prepared accordingly.

Inclusion Criteria:

• Subject or parent/legal representative is considered reliable and capable of adhering to the protocol
• Subject is male or female, and is ≥13 and <18 years of age at Visit 2/Baseline
• Subject weighs ≥40 kg at Visit 2/Baseline
• Subject's Body Mass Index (BMI) is less than the 95th percentile for his or her age at Visit 2/Baseline
• Subject meets the diagnosis of RLS based on the proposed 2011 Revised International Restless Legs Syndrome Study Group Diagnostic Criteria
• Subject's RLS symptoms cause significant distress or impairment
• At Visit 2/Baseline, subject has a Periodic Limb Movement Index (PLMI) ≥5 during at least 1 of the 5 nights prior to Baseline as measured by the activity monitors
• At Visit 2/Baseline, subject has a score of ≥15 on the IRLS Rating Scale
• At Visit 2/Baseline, subject scores ≥4 points on the Clinical Global Impression (CGI) Item 1 assessment
• Subject receiving supplemental iron has been on a stable dose for at least 3 months prior to Visit 1/Screening Period

Exclusion Criteria:

• Previously participated in this study or received previous treatment with rotigotine
• Participated in another study of an investigational medicinal product (IMP) or a medical device within the last 3 months prior to Visit 1/Screening Period or is currently participating in another study of an IMP or a medical device
• Subject's RLS symptoms are restricted only to the ankles or knees
• RLS symptoms are due to renal insufficiency (uremia) or iron deficiency anemia
• Previous treatment with dopamine agonists within a period of 14 days prior to Visit 2/Baseline or L-dopa within 7 days prior to Visit 2/Baseline
• Failed to respond to previous dopaminergic therapy
• Any medical or psychiatric condition, which in the opinion of the investigator, would jeopardize or compromise the subject's well being or ability to participate
• Subject has a lifetime history of suicide attempt or has suicidal ideation in the past 6 months
• Evidence of an impulse control disorder (ICD)
• History or current symptoms of sleep apnea, narcolepsy, sleep attacks/sudden onset of sleep, or myoclonus epilepsy
• Concomitant diseases such as peripheral neuropathy, muscle fasciculation, painful legs and moving toes, fibromyalgia, rheumatoid arthritis, or sickle cell disease
• Serum ferritin level <15 ng/mL
• Subject has not attempted at least 1 non-pharmacological intervention for the management of RLS (eg, sleep hygiene, exercise)
• Prior history of psychotic episodes
• History of chronic alcohol or drug abuse within 12 months prior Screening Period
• Clinically relevant cardiac dysfunction and/or arrhythmias
• Hemoglobin level below the lower limit of normal
• Clinically relevant renal dysfunction (serum creatinine >1.5 mg/dL)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level greater than or equal to 2 times the upper limit of normal
• History or presence of clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesion (which may be melanoma), melanoma, or a history of melanoma
• Currently receiving or has received treatment with any of the following within 28 days prior to Visit 2/Baseline: neuroleptics, antidepressants, anxiolytic drugs, opioids, monoamine oxidase (MAO) inhibitors, or sedative antihistamines
• Currently receiving treatment with any of the following: benzodiazepines, hypnotics, anticonvulsants, central alpha-adrenergic agonists, or melatonin; unless treatment is for RLS only, in which case a Wash-Out Period of at least 14 days prior to Visit 2/Baseline is required
• Currently receiving stimulant therapy for attention deficit hyperactivity disorder (ADHD); a Wash-Out Period of at least 7 days prior to Visit 2/Baseline is required
• Pregnant, nursing, or is a woman of childbearing potential who is not surgically sterile, or does not consistently use 2 combined medically acceptable methods of contraception (including at least 1 barrier method), unless not sexually active
• Unwilling to abstain from caffeine after 4pm each evening within 7 days prior to Visit 2/Baseline and for the duration of the study
• Pursues shift work or performs other continuous non-disease-related life conditions, which do not allow regular sleep at night
• Subject has a QT correction (QTc) interval of ≥500 ms at Visit 1/Screening Period or Visit 2/Baseline. Bazett's correction method must be used for the correction of the QT interval
• Symptomatic orthostatic hypotension with a decrease of blood pressure (BP) from supine to standing position of ≥20 mmHg in systolic blood pressure (SBP) or of ≥10 mmHg in diastolic blood pressure (DBP) taken from the 5 minute supine and 1 and/or 3 minute standing measurements
• 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 or eczema