Study to Investigate Pharmacokinetics (PK) of Pramipexole in Pediatric Patients Who Are Individually Optimized to Stable Pramipexole Doses for the Treatment of Idiopathic Restless Legs Syndrome (RLS)

Study Overview
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Brief Summary
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Study to determine the pharmacokinetics (PK) of pramipexole (PPX) after administration of a single dose orally (p.o.) in pediatric patients with the diagnosis of RLS

Official Title
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An Open-label Clinical Study to Investigate Pharmacokinetics (PK) of Different Doses (0.125 mg, 0.25 mg, 0.5 mg) of Pramipexole Administered Once Daily Orally in Pediatric Patients Who Are Individually Optimized to Stable Pramipexole Doses for the Treatment of Idiopathic Restless Legs Syndrome (RLS)

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: MIRAPEX® - low
* Drug: MIRAPEX® - medium
* Drug: MIRAPEX® - high


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ages 6 years to 16 years (two age groups, 6 to 11 years and 12 to 16 years, with the same number of patients if possible) Diagnosis of idiopathic Restless Legs Syndrome (RLS) according to the Clinical RLS criteria of the International Restless Legs Syndrome Study Group (IRLSSG) All 4 of the following criteria must be present: An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. (Sometimes the urge to move is present without the uncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs.) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting 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 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.) Must meet all 4 of the diagnostic criteria for adult RLS (see inclusion criterion No. 2 above) and either: The child must be able to describe the leg discomfort in their own words or The child must have 2 or 3 of the following: Sleep disturbance Periodic Limb Movements During Sleep (PLMS) index >5 per hour of sleep, or A biological parent or sibling with definite RLS Written informed consent consistent with International Conference on Harmonisation (ICH)/ Good Clinical Practice (GCP) and Local Institutional Review Board requirements for children obtained prior to any study procedures being performed Ability and willingness to comply with the study treatment regimen and to attend study assessments Must be on PPX treatment at the same evening maintenance dose for a minimum of 7 days prior to entry into this study as determined by the investigator A patient who is taking PPX but not as an evening maintenance dose may return for a repeat screening if the patient can be successfully switched and re-stabilized to an evening PPX maintenance dose Exclusion criteria: Any women of childbearing potential having a positive serum pregnancy test at screening Any women of childbearing potential not using a medically accepted method of contraceptive (Intra-Uterine Device, oral, implantable, injectable contraceptives and estrogen patch, double barrier method [spermicide + diaphragm], or abstinence at the discretion of the investigator) Patients who have a clinically significant renal disease or serum creatinine level greater than 1.0 mg/dL at screening Any of the following lab results at screening: Hemoglobin (Hgb) below the lower limit of normal (LLN), which is determined to be clinically significant Basal thyroid stimulating hormone (TSH), triiodothyronine (T3) or thyroxine (T4) clinically significantly (at the investigator's discretion) out of the normal range at screening (if not caused by substitution therapy according to the investigator's opinion) Patients with any clinically significant abnormalities in laboratory parameters at screening at the investigator's discretion Other clinically significant metabolic-endocrine, hematological, gastrointestinal disease, pulmonary disease (such as severe asthma) which in the opinion of the investigator would preclude the patient from participating in this study History or clinical signs of any neurological disease with potential to secondarily cause RLS symptoms Presence of any other sleep disorder such as Rapid Eye Movement (REM) sleep behavior disorder, narcolepsy, or sleep apnea syndrome History of schizophrenia or any psychotic disorder, history of mental disorders, or any present Axis I psychiatric disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) requiring any medical therapy History of/or clinical signs of epilepsy or seizures other than fever-related seizures in early childhood History of/or clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesions (which may be melanoma), melanoma, or a history of melanoma Any other conditions that, in the opinion of the investigator, would interfere with the evaluation of the results or constitute a health hazard for the patient Allergic response to PPX or the inactive ingredients in its tablet formulation Had previous treatment with dopamine agonists other than PPX within 14 days prior to the baseline visit Had any other medical treatment for RLS besides the study medication within 14 days prior to the baseline visit Had withdrawal symptoms of any medication at screening or at the baseline visit

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MIRAPEX® - low<br> | Drug: MIRAPEX® - low<br> <br> |
| Experimental: MIRAPEX® - medium<br> | Drug: MIRAPEX® - medium<br> <br> |
| Experimental: MIRAPEX® - high<br> | Drug: MIRAPEX® - high<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax,ss | Maximum concentration of the Pramipexole (PPX) in plasma at steady state over a uniform dosing interval (Cmax,ss). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Cmin,ss | Minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval (Cmin,ss). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Cpre,N | Predose concentration of the analyte in plasma at steady state immediately before administration of the next dose N (Cpre,N). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Cavg | Average concentration of the analyte in plasma at steady state (Cavg). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Tmax,ss | Time from dosing to maximum concentration at steady state (Tmax,ss). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Tmin,ss | Time from dosing to minimum concentration at steady state (Tmin,ss ). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| AUCτ,ss | Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval (AUCτ,ss ). | 0.25h before the drug administration on day 1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on Day 1. | 
| λz,ss | Terminal rate constant in plasma at steady state (λz,ss ). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| t1/2,ss | Terminal half-life of the analyte in plasma at steady state (t1/2,ss ). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| MRTpo,ss | Mean residence time of the analyte in the body at steady state (MRTpo,ss). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| CL/F,ss | Apparent clearance of the analyte in the plasma after extravascular administration at steady state; F = absolute bioavailability factor (CL/F,ss ). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Vz/F,ss | Apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state (Vz/F,ss ). | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 
| Ae 0-12,ss | Amount of analyte that is eliminated in urine at steady state over a time interval t1to t2 (0-12h). | 12 hours after last study drug administration on day 1 | 
| fe 0-12,ss | Fraction of administered drug excreted unchanged in urine at steady state over a time interval t1 to t2 (fe 0-12,ss ). | 12 hours after last study drug administration on day 1. | 
| CLR,ss | Renal clearance of the analyte at steady state (CLR(0-12),ss ). | 12h after last study drug administration on day 1 | 
| PTF | Peak-trough fluctuation (PTF) is defined as the difference between Cmax and Cmin divided by Cavg and multiplied with 100% at steady-state. | 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Drug Related Adverse Events | Number of patients with adverse events due to study drug. | From first drug administration until 24 hours after last study drug administration, upto 48 days | 
| Vital Signs (Systolic and Diastolic Blood Pressure) | Vital signs (Systolic and diastolic blood pressure (both supine and after standing for 1 minute)). | -0:15h(hours) pre-dose, and 0:30h, 1:00h, 2:00h, 3:00h, 5:00h, 7:00h, 12:00h, 24:00h post-dose. | 
| Vital Signs (Pulse Rate) | Vital signs (Pulse rate (both supine and after standing for 1 minute)). | -0:15h(hours) pre-dose, and 0:30h, 1:00h, 2:00h, 3:00h, 5:00h, 7:00h, 12:00h, 24:00h |