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 |
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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 | 20.1 |
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 |
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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 assess in RLS patients the efficacy and the safety profile of BP1.4979 15 mg BID. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Males or females ≥18 years
2.18 kg/m2 ≤ BMI ≤ 35 kg/m2
3.Diagnosis of idiopathic RLS based on medical history and the presence of the 5 RLS diagnostic criteria and a normal clinical examination a.An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs. b.The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting. c.The urge to move the legs and any accompanying 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 the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day. e.The occurrence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition.
4.The condition is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.
5.RLS severity score ≥ 21/40 and RLS occurring at least 3 times per week for ‘de novo’ patients or after RLS treatment wash-out.
6.Periodic Limb Movements during Sleep index > 15 for ‘de novo’ patients or after RLS treatment wash out.
7.Not taking or accepting to discontinue drug therapy or medication for RLS, antipsychotic medication, antidepressant including Selective Serotonin Reuptake Inhibitors (SSRIs) prescribed for at least 5 half-lives prior to randomization (e.g. fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, milnacipran, duloxetine) and/or any other psychotropic medication benzodiazepine (if prescribed to relief RLS) and/or anticonvulsivants (gabapentine, pregabaline) prescribed to relief RLS, for at least 5 half-lives prior to randomization and/or opiates.
8.Females of child-bearing potential must use a medically accepted effective method of birth control, agree to continue this method for the duration of the study and be negative to serum pregnancy test performed at the screening visit. Females should not be breast-feeding. Males accept to use child conception prevention method for the whole duration of the study
9.In the opinion of the investigator, the subject must have adequate support to comply with the entire study requirements as described in the protocol (e.g. transportation to and from trial site, self-rating scales, drug compliance, scheduled visits, etc).
10.Patient must have voluntarily expressed willingness to participate in this study, understand protocol procedures and have signed and dated an informed consent prior to beginning any protocol required procedures.
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E.4 | Principal exclusion criteria |
1. Any significant psychiatric illness (schizophrenia, bipolar disorder, severe depression, dementia, obsessive compulsive disorder...) or mood disorder, assessed by the Beck Depression Inventory (BDI) (exclusion if ≥ 16 and/ or item G ≠ 0).
2. Abnormal neurological examination, history or presence of chronic pain other than that associated with RLS. History of epilepsy or serious head injury. History of peripheral neuropathy. Any secondary form of RLS.
3. Clinically significant sleep apnea (Apnea Hypopnea Index >15), narcolepsy, parasomnia as an adult, circadian rhythm disorder, or secondary causes of RLS (e.g chronic renal failure/hemodialysis).
4. Other active clinically significant illness, including unstable cardiovascular, or neoplasic pathology which could interfere with the study conduct or counter-indicate the study treatments, place the subject at risk during the trial or interfere with study assessments or compromise the study participation.
5. Subject with a known history of long QTc syndrome (e.g. syncope or arrhythmia) or presenting any significant serious abnormality of the ECG (e.g. recent myocardial infarction), or QTcB interval strictly higher than 450 ms (electrocardiogram Bazett’s corrected QT interval: QTc=QT/√[60/HR]).
6. Subject with moderate hepatic impairment (transaminases > 1.5 ULN) or with renal impairment (creatinine clearance < 90 mL/min) , or with any other significant abnormality in the physical examination or clinical laboratory results (e.g positive laboratory test for Hepatitis B surface antigen (HBsAg), or anti-HIV 1/2 or anti- HCV antibodies).
7. Iron deficiency (ferritin < 50 µg/l).
8. Known hypersensitivity to the tested treatment including active substance and excipients.
9. Use of drugs likely to influence sleep architecture or motor manifestations during sleep prior to randomization without an appropriate wash-out period. These include neuroleptics, L-dopa, dopamine agonists, hypnotics, sedatives, anxiolytics, antidepressants, anticonvulsants, psychostimulant medications, steroids in the evening, barbiturates, benzodiazepine treatment and opiates to relief RLS.
10. Patient taking any prescription drug containing amphetamines.
11. Recent history (≤ 1 year) of alcohol or drug abuse, or current evidence of substance dependence or abuse as defined by DSM-IV criteria.
12. Regular consumption of large amounts of xanthine-containing substances (i.e more than 5 cups of coffee or equivalent amounts of xanthine-containing substance per day).
13. Patient participating in another study and the use of any investigational therapy within the 30 days prior to the entry in this study.
14. Patient without any medical care insurance.
15. Pregnant woman or a pregnancy detected with a positive serum pregnancy test performed at the screening visit or lactating female.
16. Male patient who wants to conceive a child for the whole duration of the study.
17. Patient under guardianship who cannot provide consent on his own.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point will be the measure of the difference from baseline (Randomization) to the end of the double blind treatment period in Periodic Limb Movements per hour of Sleep (PLMS index) measured with PolySomnoGraphy (PSG). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation performed at V2 and V3 |
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E.5.2 | Secondary end point(s) |
• The difference in IRLSRS score measured at randomization and end double blind study treatment period.
• Response to study treatment: Response to treatment will be defined by a decrease from baseline (end of wash out) of at least 50% of the International Restless Legs Syndrome Rating Scale (IRLSRS) score measured at end of double blind study treatment period.
• Parameters evaluated by Suggested Immobilization Test (SIT): - Periodic Limb Movement during Wakefulness (PLMW). - mSIT disturbance scale
• Parameters evaluated by PolySomnoGraphy (PSG): - PLMS with microaousals - Total sleep time - WASO (wake time after sleep onset)
• Clinical Global Impression-Improvement (CGI-I) scale
• Pain assessment through Visual Analog Scale for pain (VAS pain)
• Duration of efficacy maintenance above 50% reduction of IRLSRS score
• Pittsburg Sleep Quality Index (PSQI)
• Epworth Sleepiness Scale (ESS)
• Insomnia Severity Index (ISI)
• PSG comparison of the standard sleep variables (sleep latency, sleep efficacy, sleep phase distribution, etc.) between groups.
• Safety will be assessed by evaluation of adverse events, various questionnaires and vital signs (measurement of heart rate, blood pressure, and body weight) at each study visit, by physical examinations (V0 and/or V1, V2 and V3), 12-lead ECG and laboratory tests (blood chemistry, haematology, urinalysis tests, prolactin dosage and pregnancy test) at screening (V0 and/or V1) and after double blind treatment (V3).
• If at ECG Fridericia’s corrected QT interval ≥ 500 ms or if difference to baseline is ≥ 60 ms it will be required to check ECG by second measurement after lying down 10 minutes.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
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 | 5 |
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 | 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
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | 0 |