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

Conditions

Restless Legs Syndrome

Keywords

Rotigotine, Restless Legs Syndrome, RLS, Children, Adolescents

Brief summary

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).

Elshoff JP, Hudson J, Picchietti DL, Ridel K, Walters AS, Doggett K, Moran K, Oortgiesen M, Ramirez F, Schollmayer E.

2016-06-0814 citations

10.1016/j.sleep.2016.04.012

Interventions

DRUGRotigotine

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.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

13 Years to 17 Years

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame	Description
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Apparent Total Body Clearance (Cl/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 0.5 mg/24 h (2.5 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 1 mg/24 h (5 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 2 mg/24 h (10 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.
Volume of Distribution at Steady State (VSS/f) of Unconjugated Rotigotine 3 mg/24 h (15 cm^2)	0 h (predose), 1 h, 2 h, 7-12 h and 22-24 h on Day 7, 14, 21 and 28	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.

Countries

United States

Participant flow

Recruitment details

This was a multicenter study in which 42 subjects were enrolled and 24 treated at 8 sites in the USA.

Pre-assignment details

In total 42 subjects signed the informed consent and were enrolled into the study (Enrolled Set). 24 of these subjects were treated with medication. The sample size of 24 subjects was sufficient to target a 95% confidence interval and the calculation was based on a previous study. Participant Flow refers to the 24 treated subjects (Safety Set).

Participants by arm

Arm	Count
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.	24
Total	24

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Lost to Follow-up	1
Overall Study	Violation of inclusion criteria	1

Baseline characteristics

Characteristic	Rotigotine
Age, Continuous	15.3 years STANDARD_DEVIATION 1.3
Age, Customized 13 years	2 Participants
Age, Customized 14 years	6 Participants
Age, Customized 15 years	6 Participants
Age, Customized 16 years	4 Participants
Age, Customized 17 years	6 Participants
BMI (Body Mass Index)	23.388 kg/m^2 STANDARD_DEVIATION 3.133
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Height	167.39 cm STANDARD_DEVIATION 6.89
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	8 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	16 Participants
Sex: Female, Male Female	15 Participants
Sex: Female, Male Male	9 Participants
Weight	65.70 kg STANDARD_DEVIATION 10.72

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	15 / 24
serious Total, serious adverse events	0 / 24

Outcome results

Primary

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.