| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Restless Leg Syndrone - a disorder which one feels the urge to move the legs to reduce the unpleasant sensation. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058920 |
| E.1.2 | Term | Restless legs syndrome |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study was to assess the pharmacokinetics of PPX in pediatric RLS patients. The total and maximum exposure, absorption, distribution and elimination after multiple administration of low (0.125 to 0.5 mg) single daily doses of PPX for the treatment of RLS were estimated in the pediatric population. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) 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)
2) Diagnosis of idiopathic RLS according to the Clinical RLS criteria of the IRLSSG. All 4 of the following criteria had to 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.)
3) Must have met all 4 of the diagnostic criteria for adult RLS (see inclusion criterion No. 2 above) and either:
(a) The child had to be able to describe the leg discomfort in their own words or
(b) The child must have had 2 or 3 of the following:
• Sleep disturbance
• PLMS index >5 per hour of sleep, or
• A biological parent or sibling with definite RLS
4) Written informed consent consistent with ICH/GCP and Local Institutional Review Board requirements for children obtained prior to any study procedures being performed
5) Ability and willingness to comply with the study treatment regimen and to attend study assessments
6) Must have been 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
7) A patient who was 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. |
|
| E.4 | Principal exclusion criteria |
1) Any women of childbearing potential having a positive serum pregnancy test at screening
2) 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 [spermacide + diaphragm], or abstinence at the discretion of the investigator)
3) Patients who have a clinically significant renal disease or serum creatinine level greater than 1.0 mg/dL at screening
4) Any of the following lab results at screening:
• Hemoglobin (Hgb) below the lower limit of normal (LLN), which was 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 atscreening at the investigator’s discretion
5) 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
6) History or clinical signs of any neurological disease with potential to secondarily cause RLS symptoms
7) Presence of any other sleep disorder such as Rapid Eye Movement (REM) sleep behavior disorder, narcolepsy, or sleep apnea syndrome
8) History of schizophrenia or any psychotic disorder, history of mental disorders, or any present Axis I psychiatric disorder according to the DSM-IV requiring any medical therapy
9) History of/or clinical signs of epilepsy or seizures other than fever-related seizures in early childhood
10) History of/or clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesions (which may be melanoma), melanoma, or a history of melanoma
11) 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
12) Allergic response to PPX or the inactive ingredients in its tablet formulation
13) Had previous treatment with dopamine agonists other than PPX within 14 days prior to the baseline visit
14) Had any other medical treatment for RLS besides the study medication within 14 days prior to the baseline visit
15) Had withdrawal symptoms of any medication at screening or at the baseline visit |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints were the plasma PK parameters:
• Cmax,ss (maximum concentration of the analyte in plasma at steady state over a uniform dosing interval)
• Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval)
• Cpre,N (predose concentration of the analyte in plasma at steady state immediately before administration of the next dose N)
• Cavg (average concentration of the analyte in plasma at steady state)
• tmax,ss (time from dosing to maximum concentration at steady state)
• tmin,ss (time from dosing to minimum concentration at steady state)
• AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval)
• λz,ss (terminal rate constant in plasma at steady state)
• t1/2,ss (terminal half-life of the analyte in plasma at steady state)
• MRTpo,ss (mean residence time of the analyte in the body at steady state)
• CL/F,ss (apparent clearance of the analyte in the plasma after extravascular administration at steady state; F = absolute bioavailability factor)
• Vz/F,ss (apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state)
• Ae 0-t2,ss (amount of analyte that is eliminated in urine at steady state over a time interval t1to t2)
• fe 0-t2,ss (fraction of administered drug excreted unchanged in urine at steady state over a time interval t1 to t2)
• CLR,ss (renal clearance of the analyte at steady state)
• PTF (peak-trough fluctuation) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoints were evaluated 0.5, 1, 2, 3, 5, 7 hr, then 12 hr post dose (the next morning) and 24 hr post dose (the next evening). |
|
| E.5.2 | Secondary end point(s) |
| Secondary endpoints included pulse rate, systolic and diastolic blood pressure (supine and standing), and adverse event reporting. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints have been evaluated at each visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject undergoing the trial |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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