A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo

Study Overview
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Brief Summary
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Proof of concept, double-blind, randomized, placebo-controlled trial with d-methadone proposed for the first time for use in the treatment of patients diagnosed with primary, moderate to very severe Restless Legs Syndrome (RLS). Its glutamatergic mechanism of action might be effective on RLS arousal pattern and sleep disturbance which highly impair the quality of life of RLS's patients. Patients will take the study drug/placebo once a day for 30 consecutive days.

Official Title
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A Proof of Concept, Multicentre, Phase 2, Double-Blind, Randomized, Placebo-Controlled Study on the Efficacy, Safety and Tolerability of d-Methadone in Moderate to Very Severe Restless Legs Syndrome With Periodic Limb Movements: the Glu-REST Study

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: D-methadone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of primary RLS. Moderate to very severe RLS defined as IRLS-RS score > 10. Written informed consent. Willingness and ability to participate in the trial Exclusion Criteria: Positive history of known causes of secondary RLS. Any other concomitant treatment for RLS (wash-out period: at least 7 days). Moderate-severe sleep apnea defined as Apnea Hypopnea Index ≥ 15. History or presence of clinically significant abnormality as assessed by neurological examination which in the opinion of the Investigator would jeopardize the safety of the patients or the validity of the study results. Evidence of clinically significant hepatic or renal impairment History or family history of sudden unexplained death or long QT syndrome. Any 12-lead ECG with demonstration of QTc ≥ 450 msec or a QRS interval ≥ 120 msec at Screening. Concomitant use of psycho-drugs dopamine agonists and opioids (wash-out period: at least 7 days). History or presence of any condition in which an opioid is contraindicated History of allergy or hypersensitivity to methadone or related drugs. Any clinically significant neurological, sleep, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, chronic pain, psychiatric or gastrointestinal disorder. Women who are pregnant or breast feeding. Inability to follow the procedures of the study, (e.g. due to language problems, psychological disorders, dementia, etc. of the participant). Previous enrolment into the current study. Enrolment of the investigator, his/her family members, employees and other dependent persons. Participation in another study with investigational drug within the 30 days preceding and during the present study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 25 mg d-methadone<br>The experimental drug is a tablet formulation of d-methadone HCl in dose strength of 25 mg. | Drug: D-methadone<br>* Patients will take one tablet of 25 mg d-methadone once daily at 6 pm over a period of 30 days<br>* Other names: esmethadone, dextromethadone, REL-1017;|
| Placebo Comparator: Placebo<br>The placebo is an exact match to the active tablets in size, color and marking without the active ingredient d-methadone HCl. | Other: Placebo<br>* Patients will take one tablet of placebo once daily at 6 pm over a period of 30 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of d-methadone | The percentage of responders to d-methadone treatment. A responder is defined as patient who has ≥ 50% reduction in the International RLS Rating Scale (IRLS-RS) score from baseline to end of the 30-day treatment period. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insomnia severity | Change in insomnia severity from baseline to the end of 10-day dosing period and to end of the treatment period assessed by a using the Insomnia Severity Index (ISI) | 10 and 30 days | 
| Change in Quality of life | Change in quality of life from baseline to the end of 10-day dosing period and to end of the treatment period assessed assessed by a using the Restless Legs Syndrome Quality of Life Questionnaire (RLSQoL) | 10 and 30 days | 
| Periodic limb movements of sleep index | Change in Periodic limb movements of sleep (PLMS) index from baseline to end of 10-day dosing period measured by means of polysomnography recording | 10 days | 
| Actigrafic parameters | Change from baseline to the end of 10-day dosing period and to end of the treatment period on Total Sleep Time, Sleep Latency and Sleep Efficacy acquired assessed by actigraphy with measurements performed one week prior to the start of treatment, during the 10-day dosing period and one week at the end of the treatment. | 10 and 30 days |