| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10058920 |
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| 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 |
| to demonstrate that rotigotine is effective in subjects with idiopathic RLS based on the PLMI (PLMs/total time in bed) as measured by PSG |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Subject is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent.
2. Subject understands the investigational nature of the trial and is willing and able to comply
with the trial requirements. Subject is willing to accept that he/she might be treated with placebo during the treatment period.
3. Subject is able to apply/remove the trial patch correctly and consistently.
4. Subject is male or female, and is ≥18 and ≤75 years of age.
5. Subject meets the diagnosis of idiopathic RLS based on the 4 essential clinical features according to the IRLSSG (Allen et al, 2003):
a. An urge to move legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (The urge to move can be present without uncomfortable
sensations. Arms or other body parts can also be affected.).
b. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting.
c. 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.
d. 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.).
6. Subject has had an initial response to previous dopaminergic treatment for RLS or has had no previous dopaminergic treatment (ie, de novo).
7. The subject’s body mass index (BMI) is ≥18kg/m2 and ≤35kg/m2.
8. At Baseline (Visit 2), subject has a score of ≥15 on the IRLS Rating Scale (indicating moderate to severe RLS).
9. At Baseline (Visit 2), subject scores ≥4 points on the CGI Item 1 assessment (indicating mildly ill).
10. At Baseline (Visit 2), subject scores ≥15 PLM/h on the PLMI based on PSG (recorded during the second night) as assessed by the investigator.
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| E.4 | Principal exclusion criteria |
1. Subject has secondary RLS (eg, due to renal insufficiency [uremia], iron deficiency anemia, or rheumatoid arthritis).
2. Subject has secondary RLS associated with previous or concomitant therapy with dopamine D2 receptor antagonists, butyrophenones, metoclopramide, atypical antipsychotics (eg, olanzapine), tri- and tetra-cyclic antidepressants, mianserine, lithium or H2-blockers (eg, cimetidine), or due to withdrawal from drugs such as anticonvulsants, benzodiazepines, barbiturates, and other hypnotics.
3. Subject has a history of sleep disturbances like sleep apnea syndrome (including obstructive sleep apnea), narcolepsy, sleep attacks/sudden onset of sleep, or myoclonus epilepsy either observed during PSG (local PSG evaluations) or evidenced by subject history.
4. Subject has additional clinically relevant concomitant diseases such as attention deficit hyperactivity disorder, polyneuropathy, akathisia, claudication, varicosis, muscle fasciculation, painful legs and moving toes, or radiculopathy.
5. Subject has other central nervous system diseases such as Parkinson’s disease, dementia, progressive supranuclear paresis, multisystem atrophy, Huntington’s Chorea, amyotrophic lateral sclerosis, or Alzheimer’s disease.
6. Subject has a prior history of psychotic episodes.
7. Subject has a history of chronic alcohol or drug abuse within the last 12 months.
8. Subject has any medical or psychiatric condition, which in the opinion of the investigator, can jeopardize or would compromise the subject’s ability to participate in this trial.
9. Subject has clinically relevant cardiac dysfunction and/or arrhythmias (eg, suspected conduction system dysregulations, second or third degree AV block, complete left or right bundle branch block, sick-sinus-syndrome, New York Heart Association Class III or IV congestive heart failure, or has had a myocardial infarction within 12 months prior to Screening [Visit 1]).
10. Subject has clinically relevant venous or arterial peripheral vascular disease.
11. Subject has clinically relevant renal dysfunction (serum creatinine >2.0mg/dL).
12. Subject has clinically relevant hepatic dysfunction (total bilirubin >2.0mg/dL or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than 2 times the upper limit of the reference range).
13. Subject has a malignant neoplastic disease requiring therapy within 12 months prior to Screening (Visit 1).
14. Subject is currently receiving treatment with any of the following drug classes: neuroleptics, hypnotics, antidepressants, anxiolytic drugs, anticonvulsive therapy, budipine, dopamine antagonist anti-emetics (except domperidone), opioids, benzodiazepines, monoamine oxidase (MAO) inhibitors, catechol-O-methyl-transferase (COMT) inhibitors, sedative antihistamines, psychostimulates, or amphetamines. If subject has received such therapy, a washout period of at least 7 days prior to Baseline (Visit 2) is required before starting treatment in this trial.
15. Subject is pregnant, nursing, or is a woman of child-bearing potential who is not surgically sterile, 2 years postmenopausal, or does not consistently use 2 combined effective methods of contraception, including at least 1 barrier method, unless sexually abstinent.
16. Subject pursues shift work or performs other continuous non-disease-related life conditions which do not allow regular sleep at night.
17. At Screening (Visit 1), subject has a QT interval in ECG, corrected for heart rate (QTc), interval of ≥500ms or the subject has an average QTc interval ≥500ms at Baseline (Visit 2) as reported by the automatic or manually over-read central reading results. The average is taken from 3 ECGs performed at least 15 minutes apart. Bazett’s correction method will be used for the correction of the QT interval by the central ECG evaluations.
18. At Screening (Visit 1) or Baseline (Visit 2), subject has symptomatic orthostatic hypotension with a decrease of blood pressure (BP) from supine to standing position of ≥20mmHg in systolic BP or of ≥10mmHg in diastolic BP taken from the 5 minute supine, and 1 and/or 3 minute standing measurements at Visit 1 or Visit 2, or supine SBP <105mmHg at Baseline (Visit 2).
19. Subject has had previous treatment with dopamine agonists within a period of 28 days prior to Baseline (Visit 2), or L-dopa within 7 days prior to Baseline (Visit 2).
20. Subject has a medical history indicating intolerability to prior dopaminergic therapy (if pretreated).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary variable:
The primary variable is the reduction of PLMI at the end of the Maintenance Period compared to Baseline. PLMI data will be obtained from PSGs.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| The end of the trial is defined as the date of the last visit of the last patient undergoing the trial |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
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