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

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 byneurological examination which in the opinion of the Investigator would jeopardizethe 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 atScreening.

• Concomitant use of psycho-drugs dopamine agonists and opioids (wash-out period: atleast 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, psychiatricor 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 dependentpersons.

• Participation in another study with investigational drug within the 30 dayspreceding and during the present study.