| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Restless Legs Syndrome in patients with End Stage Renal Disease (ESRD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Restless Legs Syndrome in patients with End Stage Renal Disease (ESRD) |
|
| 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 | SOC |
| E.1.2 | Classification code | 10029205 |
| E.1.2 | Term | Nervous system disorders |
| 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 this trial is to demonstrate superiority of rotigotine against placebo in subjects with RLS and ESRD requiring hemodialysis. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to investigate the effect of rotigotine on quality of life and sleep in this patient population. In addition, safety and tolerability of rotigotine will be evaluated. |
|
| 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 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 patches correctly.
4. Subject is male or female, and is ≥ 18 and ≤ 85 years of age.
5. Subject has a body mass index (BMI) of ≥ 18kg/m2 and 40kg/m2.
6. Subject has end-stage renal disease (ESRD) requiring hemodialysis and has been on a regular dialysis schedule for at least 3 months prior to Screening (Visit 1)
7. Subject has hemoglobin concentration of ≥ 8g/dL(4.97mmol/L) at Screening (Visit 1)
8. Subject has ferritin concentration of ≥ 100ng/mL at Screening (Visit 1)
9. Subject has a diagnosis of RLS based on the 4 cardinal diagnostic clinical features according to the International Restless Legs Syndrome Study Group (IRLSSG):
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.).
10. Subject has had an initial response to previous dopaminergic treatment for RLS, or has had no previous dopaminergic treatment (ie, de novo).
11. At Baseline (Visit 2), subject has a score of ≥15 points on the IRLS (indicating moderate to severe RLS).
12. At Baseline (Visit 2), subject has a score of ≥11 points on the RLS-DI (Diagnostic Index).
13. At Baseline (Visit 2), subject has a score of ≥4 points on the CGI Item 1 assessment (indicating moderately ill).
14. At Baseline (Visit 2), subject scores ≥15 PLMs per hour on the PLMI based on PSG (recorded during the second night) as assessed by the investigator. |
|
| E.4 | Principal exclusion criteria |
2. Subject has narcolepsy or other hypersomnia (including sleep attacks/sudden onset of
sleep), either observed during local PSG, Multiple Sleep Latency Test (MSLT), or
Maintenance of Wakefulness Test (MWT) or evidenced by subject history.
3. Subject has clinically relevant polyneuropathy or varicosis which cannot be clearly differentiated from RLS symptoms in the opinion of the Investigator.
4. Subject has additional clinically relevant concomitant diseases, such as attention deficit hyperactivity disorder, akathisia, painful legs and moving toes.
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 evidence of an impulse control disorder according to the modified Minnessota Impulsive Disorders Interview (mMIDI) at Screening (Visit 1).
7. 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 C-SSRS at Screening. (Visit1) or Baseline (Visit 2).
8. Subject has a prior history of psychotic episodes.
9. Subject has a history of chronic alcohol or drug abuse within the last 12 months.
10. Subject has any medical or psychiatric condition, which in the opinion of the investigator, can jeopardize or would compromise the subject’s well-being or ability to participate in this trial.
11. Subject has a history of symptomatic (not asymptomatic) orthostatic hypotension in the 6 months prior to Baseline (Visit 2).
12. Subject has clinically relevant cardiovascular disease which in the opinion of the Investigator could compromise the subject’s well-being or ability to participate in this trial.
13. Subject has clinically relevant venous or arterial peripheral vascular disease.
14. Subject has a malignant neoplastic disease requiring therapy within 12 months prior to Screening (Visit 1).
15. Subject is currently receiving treatment with any of the following drug classes: neuroleptics, norepinephrine and dopamine reuptake inhibitors (bupropion), gabapentin, budipine, dopamine antagonist antiemetics (except domperidone), opioids, monoamine oxidase (MAO) inhibitors, catechol O methyltransferase (COMT) inhibitors, or psychostimulants (eg, 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.
16. 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.
17. Subject pursues shift work or performs other continuous non-disease-related life conditions which do not allow regular sleep at night.
18. Subject has had previous treatment with dopamine agonists within a period of 14days prior to Baseline (Visit 2), or L-dopa within 7 days prior to Baseline (Visit 2).
19. Subject has a medical history indicating intolerability to dopaminergic therapy (if pre-treated) or has experienced augmentation when previously treated with any dopaminergic agent.
20. Subject has received previous treatment with rotigotine.
21. Subject has participated in another trial of an investigational drug within the last 28 days prior to Baseline (Visit 2) or is currently participating in another trial of an investigational drug.
22. Subject has a known hypersensitivity to any of the components of the trial medication, such as a history of significant skin hypersensitivity to adhesives, known hypersensitivity to other transdermal medications or has unresolved contact dermatitis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Reduction of the Periodic Limb Movements Index (PLMI) at the end of the Maintenance Period compared to Baseline in terms of the ratio from Baseline to the end of the 2-week Maintenance Period in PLMI (periodic limb movements [PLMs]/total time in bed) as
measured by PSG |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline to the end of the 2-week Maintenance Period |
|
| E.5.2 | Secondary end point(s) |
• PLMI (PLMs/total time in bed)
• International Restless Legs Scale (IRLS) sum score
• Clinical Global Impressions (CGI)-Item 1score
• Individual RLS-6 Rating Scales
• Periodic Limb Movement during Sleep Arousal Index (PLMSAI)
• Sleep efficiency (%)
• RLS-QoL
• SF-36 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary variables will be measured as Change from Baseline to the end of the 2-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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Finland |
| France |
| Germany |
| Italy |
| United States |
|
| 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 (LVLS) |
|
| 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 | 1 |
| 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 | 1 |
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