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

A Multicenter, Open-Label, 2-Group, Dose Escalation Study of Monotherapy Administration of Rotigotine in Pediatric Subjects With Idiopathic Restless Legs Syndrome

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

Study Overview

• Status: Completed
• Conditions: Restless Legs Syndrome
• Intervention / Treatment: Drug: Rotigotine

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States
      • Sp1004 006
  • California
    • Los Angeles, California, United States
      • Sp1004 012
    • Orange, California, United States
      • Sp1004 009
  • District of Columbia
    • Washington, District of Columbia, United States
      • Sp1004 005
  • Florida
    • Spring Hill, Florida, United States
      • Sp1004 014
  • Indiana
    • Indianapolis, Indiana, United States
      • Sp1004 013
  • Louisiana
    • Destrehan, Louisiana, United States
      • Sp1004 001
  • Missouri
    • Saint Louis, Missouri, United States
      • Sp1004 015
  • New York
    • West Seneca, New York, United States
      • Sp1004 007
  • Ohio
    • Cincinnati, Ohio, United States
      • Sp1004 002
  • Pennsylvania
    • West Chester, Pennsylvania, United States
      • Sp1004 016
  • Texas
    • Austin, Texas, United States
      • Sp1004 003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 hypersensitive

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rotigotine; In the Titration Period a subject received the first dose of rotigotine then the dose was increased weekly by a dose step over 4 weeks.	Drug: Rotigotine; Rotigotine transdermal patch: Dose (size): 0.5 mg/24 h (2.5 cm^2)- 1 mg/24 h (5 cm^2)- 2 mg/24 h (10 cm^2)- 3 mg/24 h (15 cm^2) The patch has to be applied continuously for 24h. After 24h, the patch has to be removed and a new one applied.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)	CL/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)	VSS/f was calculated for each subject treated with rotigotine derived from the concentrations of unconjugated rotigotine measured in plasma. For the primary variables the parametric point estimator for each dose step and the 95% CI was calculated using the least-squares (LS) means and the root mean square of error from the ANOVA of the log-transformed data with subsequent exponential transformation.	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28

Collaborators and Investigators

• Sponsor: UCB BIOSCIENCES, Inc.
• Investigators: Study Director: UCB Clinical Trial Call Center, 1-877-822-9493 (UCB)

Publications and helpful links

General Publications

• Elshoff JP, Hudson J, Picchietti DL, Ridel K, Walters AS, Doggett K, Moran K, Oortgiesen M, Ramirez F, Schollmayer E. Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis-Ekbom disease). Sleep Med. 2017 Apr;32:48-55. doi: 10.1016/j.sleep.2016.04.012. Epub 2016 Jun 8.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: December 16, 2011
• First Submitted That Met QC Criteria: December 16, 2011
• First Posted (Estimate): December 20, 2011

Study Record Updates

• Last Update Posted (Actual): April 4, 2018
• Last Update Submitted That Met QC Criteria: March 8, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Adolescents; Children; Restless Legs Syndrome; Rotigotine; RLS
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dopamine Agonists; Dopamine Agents; Rotigotine
• Other Study ID Numbers: SP1004; 2014-004383-37 (EudraCT Number)