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

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

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.

Study Overview

• Status: Suspended
• Conditions: Restless Legs Syndrome
• Intervention / Treatment: Drug: D-methadone; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy
    • Sleep Center, IRCCS San Raffaele
• Switzerland
  • Bern, Switzerland
    • Schlaf-Wach-Epilepsie Zentrum, Inselspital
  • Chur, Switzerland, 7000
    • Neurologie / Schlaflabor Kantonsspital Graubünden
  • Lugano, Switzerland, 6900
    • Sleep Center, Neurocenter of Southern Switzerland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mauro Manconi
• Collaborators: Clinical Trial Unit Ente Ospedaliero Cantonale
• Investigators: Principal Investigator: Mauro Manconi, Prof. MD, Ente Ospedaliero Cantonale, Neurocenter of Southern Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2022
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: October 29, 2019
• First Submitted That Met QC Criteria: October 29, 2019
• First Posted (Actual): October 30, 2019

Study Record Updates

• Last Update Posted (Actual): March 13, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Parasomnias; Restless Legs Syndrome; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; D-methadone
• Other Study ID Numbers: NSI-RLS-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No