| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Restless Legs Syndrome (RLS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Restless Legs Syndrome (RLS) |
|
| 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 | 14.1 |
| 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 is to demonstrate that rotigotine decreases the number of elevations of nocturnal Blood Pressure (BP) associated with Periodic Limb Movements (PLMs) in patients with idiopathic Restless Legs Syndrome (RLS). |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to examine effects of rotigotine on the total number of elevations of nocturnal BP, on standard measures of cardiovascular risk surrogate markers, on standard RLS measures of disease severity, and on quality of life (QoL) measurements. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is informed and given ample time and opportunity to think about her/his participation and give her/his written informed consent.
2. Subject understands the investigational nature of the study and is willing and able to comply with the study 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 study patch correctly.
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 International Restless Legs Syndrome Study Group (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 a score of ≥11 on the RLS-Diagnostic Index (RLS-DI) (Benes and Kohnen, 2009).
7. Subject has an initial response to previous dopaminergic treatment for RLS or has no previous dopaminergic treatment (ie, de novo).
8. The subject’s body mass index (BMI) is ≥18kg/m2 and ≤35kg/m2.
9. At Baseline (Visit 2), subject has a score of ≥15 on the IRLS (indicating moderate to severe RLS).
10. At Baseline (Visit 2), subject has a score of ≥4 points on the CGI Item 1 assessment (indicating moderately ill).
11. At Baseline (Visit 2), subject has a score of ≥15 PLM/h on the PLMI based on polysomnography (PSG) (recorded during the second night) as assessed by the investigator.
12. Subjects are on a concomitant dose of antihypertensives that is at a stable dose for at least 4 weeks prior to Baseline (Visit 2) and
hypertension is reasonably controlled while the subject agrees to continue at this dose for the duration of the study, or subject has not
received concomitant treatment with antihypertensives for at least 4 weeks prior to Baseline (Visit 2) and does not intend to start such use during the study.
|
|
| E.4 | Principal exclusion criteria |
1. Subject has RLS due to renal insufficiency (uremia), iron deficiency anemia, or rheumatoid arthritis.
2. Subject has RLS associated with previous or concomitant therapy with dopamine D2 receptor antagonists, butyrophenones, metoclopramide, atypical antipsychotics (eg, olanzapine), tri- and tetra-cyclic antidepressants, mianserine, or 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, such as 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 uncontrolled hypertension according to the judgment of the investigator.
5. 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.
6. 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.
7. Subject has a prior history of psychotic episodes.
8. Subject has a history of chronic alcohol or drug abuse within the previous 12 months.
9. 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 study.
10. Subject has clinically relevant cardiac dysfunction and/or arrhythmias (eg, suspected conduction system dysregulations, second or third degree atrioventricular block, complete left or right bundle branch block, sick sinus syndrome, New York Heart Association Class III or IV congestive heart failure, or had a myocardial infarction within
12 months prior to Screening [Visit 1]).
11. Subject has clinically relevant venous or arterial peripheral vascular disease.
12. Subject has a malignant neoplastic disease requiring therapy within 12 months prior to Screening (Visit 1).
13. Subject is currently receiving treatment with any of the following drug classes: neuroleptics, hypnotics, antidepressants, anxiolytic drugs, anticonvulsive therapy, budipine, dopamine antagonist antiemetics (except domperidone), opioids, benzodiazepines, monoamine oxidase (MAO) inhibitors, catechol-O-methyltransferase
(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 study.
14. Subject is pregnant, nursing, or is a woman of childbearing 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.
15. Subject is a shift worker or performs other continuous non–disease-related life conditions which do not allow regular sleep at night.
16. At Screening Visit (Visit 1) or Baseline Visit (Visit 2), subject has symptomatic orthostatic hypotension with a decrease of 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 systolic BP <105mmHg at Baseline (Visit 2).
17. Subject is treated with dopamine agonists within a period of 14 days prior to Baseline (Visit 2) or L-dopa within 7 days prior to Baseline (Visit 2).
18. Subject has a medical history indicating intolerability to prior dopaminergic therapy (if pretreated).
19. Subject has received previous treatment with rotigotine.
20. Subject has participated in another study of an investigational drug or device within the 28 days prior to Visit 2 (Baseline) or is currently participating in another study of an investigational drug.
21. Subject has a known hypersensitivity to any of the components of the study medication, such as a history of significant skin hypersensitivity to adhesives, known hypersensitivity to other transdermal medications, or has unresolved contact dermatitis.
22. Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening (Visit 1) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline in the number of elevations of systolic BP during the night that are associated with Periodic Limb Movements |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| end of the 4-week Maintenance Period |
|
| E.5.2 | Secondary end point(s) |
• Change from Baseline in the total number of elevations of systolic BP during the night
• Change from Baseline in the Periodic Limb Movements Index (PLMI)
• Change from Baseline in the International Restless Legs Syndrome Rating Scale (IRLS)
• Change from Baseline in RLS-QoL
• Clinical Global Impressions (CGI) Item 2 (change of condition)
• Clinical Global Impressions Item 1 (severity of illness)
• Clinical Global Impressions Item 3 (therapeutic efficacy)
• Change from Baseline in Restless Legs Syndrome-6 Rating Scales (RLS-6)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
end of the 4-week Maintenance Period
|
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | No |
| 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) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
| The end of the study is defined as the date of the final visit of the last subject in the study. |
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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