| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038741 |
| E.1.2 | Term | Restless leg syndrome |
|
| 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 assess the efficacy of a fixed dose of pregabalin to placebo during the first 12 week treatment period in subjects with RLS.
• To compare the rate of augmentation of a fixed dose of pregabalin to 2 fixed doses of pramipexole over 9 or 12 months in subjects with RLS.
|
|
| E.2.2 | Secondary objectives of the trial |
•To assess the comparability of efficacy of pregabalin and pramipexole in treating
symptoms of RLS with pregabalin or pramipexole during the first 12wks and beyond through end of the study
•To assess the severity of augmentation associated with pregabalin or pramipexole
treatment
•To assess the tolerability and safety of pregabalin and pramipexole treatment over
1yr
•To assess the impact of pregabalin and pramipexole treatment on subjective sleep
parameters over 1yr
•To assess the impact of pregabalin and pramepexol treatment on next day impact over 1yr
•To assess the impact of pregabalin and pramepexol treatment on mood as compared to placebo during the first
12wks
•To assess the impact of pregabalin and pramipexole treatment on quality of life over 1yr
•To assess the impact of pregabalin and pramipexole treatment on limb pain during the first 12wks
•To assess the impact of pregabalin and pramipexole treatment on work productivity
and activity impairment over 1yr |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following criteria to be eligible to participate in the study:
1. Diagnosis of RLS is to be made by a Physician with experience and/or training in RLS. Idiopathic RLS with the presence of all four clinical manifestations of RLS:
• Urge to move the legs usually with dysesthesias: 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);
• Onset or exacerbation with rest: The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting;
• Relief with movement: The urge to move or unpleasant sensations are partially or totally relieved by movements, such as walking or stretching, at least as long as the activity continues;
• Circadian pattern: 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);
• The following instruments will be utilized to aid the diagnosis:
• Medical history and/or RLS treatment history.
• Cambridge-Hopkins Restless Legs Syndrome Short Form Diagnostic Questionnaire (RLS-SFDQ-9) – entered by the subjects.
• RLS-Hening Clinical Diagnostic Interview (RLS-HCDI) – conducted and signed-off by the Investigator. Only subjects with a diagnosis of “Definite RLS” on the RLS-HCDI can be considered to continue with the screening process.
2. RLS symptoms must occur predominantly in the evening (between the hours of 17:00 to 07:00).
3. A history or the presence of RLS symptoms for at least 6 months.
4. An International Restless Leg Scale (IRLS) total score ≥15 at beginning of placebo run-in (1 week prior to Baseline) and end of placebo run-in (Baseline).
5. Have ≥15 nights with RLS symptoms in the month prior to Screening. Subjects receiving RLS therapy at the time of Screening are to have had ≥15 nights per month with RLS symptoms prior to initiation of this treatment. Have ≥2 nights with RLS symptoms during the week of placebo run-in.
6. Both genders. Age 18 years or older.
7. Evidence of a personally signed and dated Informed Consent Document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects may not participate in the study if they meet any of the following criteria:
1. Any secondary form of RLS which is primarily attributable to other conditions, eg, end stage renal disease, iron-deficiency anemia.
2. Current augmentation due to RLS treatment, or pramipexole-caused clinically significant augmentation within 6 weeks of the Screening Visit. Clinically significant augmentation is defined as the subject experiences symptoms that are severe enough to impact the subject’s daily life and/or requires an alteration of treatment, eg, change to another class of medication.
3. Requiring regular (more than 2 times a week within 3 months of screening visit) medication treatment for daytime RLS symptoms (between the hours of 07:00 to 17:00).
4. Placebo responders as defined by a >50% improvement in RLS symptoms, ie, decrease of the total score in IRLS Scale between beginning of placebo run in (1 week prior to Baseline) and end of placebo run-in (Baseline Visits).
5. Any symptomatic neuropathies or current diagnosis of clinically relevant concomitant conditions that may confound clinical assessments of RLS and/or severe enough to disturb sleep, for example, painful leg and moving toes syndrome.
6. Clinically significant lumbar radiculopathy or central spinal stenosis by history or examination.
7. Presence of severe central nervous degenerative diseases such as Parkinson’s disease, dementia, progressive supranuclear paresthesia, multisystem atrophy, Huntington Chorea, amyotrophic lateral sclerosis, or Alzheimer’s disease.
8. History or presence of a severe sleep disorder, especially those with difficulty falling and/or staying asleep, that may confound assessments (Apnea/Hypopnea Index greater than 20 if a sleep study has been previously performed) at the Screening or Baseline Visits. With mild to moderate sleep apnea, a subject may be eligible to participate the study. However, an AHI must be <20 without aid of continuous positive airway pressure therapy
(CPAP) if a sleep study has been previously performed.
9. Use of medications likely to influence sleep architecture or motor manifestations during sleep prior to the Baseline Visit (BL) without an appropriate washout period. Refer to Appendix 1 for the list of exclusionary medications. These include neuroleptics, hypnotics, sedatives, antidepressants, anxiolytics, anticonvulsants,
psychostimulantmedications, barbiturates and opioids. Note: Use of serotonin selective reuptake inhibitor (SSRI) antidepressants at a stable dose for minimum 6 months prior to Screening are allowed to enter the study, if discontinuation is determined against the subject's well being. However, subject must be able to sustain the same treatment and dose level throughout the trial per investigator's discretion. Use of selective (serotonin) norepinephrine reuptake inhibitor (SNRI) is not permitted during the study.
10. Clinically significant liver disease, or an elevation in either bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) levels >3 times the upper limit of normal value (ULN).
11. Clinically significant renal disease, or creatinine clearance level <60 mL/min (estimated by Cockroft Gault method).
12. Any other clinically significant condition (eg, cardiac dysfunction, active neoplasm, uncorrected hypothyroidism or hyperthyroidism) or laboratory assay abnormality.
13. Failure to respond positively to dopaminergic agents, gabapentin or pregabalin in treating RLS according to medical history.
14. Known hypersensitivity to any components of the trial medication or similar drugs.
15. Serum ferritin below 15µg/L.
16. Employment hours disruptive to the normal circadian sleep wake cycle such as nighttime or variable rotating shifts.
17. Imminent suicide risk by medical history and/or by assessment using C-SSRS. If any risk is identified and yet the subject is considered suitable to participate in the trial per Investigator's judgment, a risk assessment narrative must be constructed by a mental health professional to fulfill the eligibility requirement for participation.
18. Pregnant or lactating women, or women with child bearing potential who are not surgically sterile, two years postmenopausal, or do not practice two combined methods of medically acceptable forms of contraception.
19. Participating in other investigational drug studies or having received other investigational drugs within the previous 30 days of the Screen Visit.
20. Participated in past/concurrent pregabalin RLS studies, eg, protocols A0081183, A0081184 and A0081185, or any Investigator Initiated Research study
21. Current or history of chronic alcohol or drug abuse within the past 12 months. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Changes from baseline in RLS symptom severity using the International Restless Leg Group Rating Scale (IRLS) total score for efficacy assessment;
• The proportion of subjects responding to treatment using the Clinical Global
Impression – Improvement (CGI-I) scale for efficacy assessment. Responders are
defined as those who report CGI-I scores of “very much improved” or “much improved”;
• Rate of augmentation over 9 or 12 months as determined by the centralized
Adjudication Board by reviewing all cases that passed a set of assessment for
potential augmentation. The assessment will rely upon a set of criteria including:
1. The Structured Interview for Diagnosis of Augmentation during RLS treatment
(SIDA-RLS) based on augmentation diagnostic criteria established by Allen et al, in 2003; or
2. Augmentation Severity Scale (ASRS); or
3. Clinical judgment that augmentation might be present. |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 38 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 14 |
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