Restless Legs SyndromePhase 2Glu-RESTNCT04145674
A Proof of Concept, Phase 2, Double-blind, Randomized Trial With d-Methadone Product Versus Placebo
A Phase 2 study testing D-methadone in people with Restless Legs Syndrome, run by Mauro Manconi at 4 sites in 2 countries.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Restless Legs Syndrome
- What is being tested?
- D-methadone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 4 sitesin 2 countries
- Study dates
- 22 Oct 2022to 30 Dec 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
Switzerland3 sites
Schlaf-Wach-Epilepsie Zentrum, Inselspital
Bern
Neurologie / Schlaflabor Kantonsspital Graubünden
Chur, 7000
Sleep Center, Neurocenter of Southern Switzerland
Lugano, 6900
About this study
Official title: 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.
- Conditions
- Restless Legs Syndrome
- Being tested
- D-methadone, Placebo
- Medical subject headings
- Restless Legs Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
D-methadoneDrug
Also called esmethadone, dextromethadone, REL-1017
Patients will take one tablet of 25 mg d-methadone once daily at 6 pm over a period of 30 days
PlaceboOther
Patients will take one tablet of placebo once daily at 6 pm over a period of 30 days
| Study group | Role | What they receive |
|---|---|---|
| 25 mg d-methadone | Experimental | The experimental drug is a tablet formulation of d-methadone HCl in dose strength of 25 mg. Receives: Drug: D-methadone |
| Placebo | Placebo comparator | The placebo is an exact match to the active tablets in size, color and marking without the active ingredient d-methadone HCl. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 days
Secondary outcomes (4)
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)
Measured: 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)
Measured: 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
Measured: 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.
Measured: 10 and 30 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Oct 2019
- Study start22 Oct 2022
- Primary completion30 Dec 2026 (estimated)
- Study completion30 Dec 2026 (estimated)
Why it stopped: budget issues
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Restless Legs SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mauro Manconi
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Trial Unit Ente Ospedaliero Cantonale
- Responsible party
- Sponsor-investigator, Mauro Manconi, Ente Ospedaliero Cantonale, Bellinzona
- Investigators
- Mauro Manconi, Prof. MD, Principal investigator, Ente Ospedaliero Cantonale, Neurocenter of Southern Switzerland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04145674
- Sponsor's protocol ID
- NSI-RLS-001
- Acronym
- Glu-REST
- Status last verified
- Mar 2026
- First submitted
- 29 Oct 2019
- Last updated
- 13 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT04145674
- Acronym / sponsor ID
- Glu-REST / NSI-RLS-001
- Conditions
- Restless Legs Syndrome
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: budget issues
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Mauro ManconiUniversity, hospital or other
- Collaborators
- Clinical Trial Unit Ente Ospedaliero Cantonale
- Study start
- 22 Oct 2022 (actual)
- Primary completion
- 30 Dec 2026 (estimated)
- Study completion
- 30 Dec 2026 (estimated)
- First posted
- 30 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 25 mg d-methadone | Experimental | Drug: D-methadoneThe experimental drug is a tablet formulation of d-methadone HCl in dose strength of 25 mg. |
| Placebo | Placebo comparator | Other: PlaceboThe placebo is an exact match to the active tablets in size, color and marking without the active ingredient d-methadone HCl. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| D-methadoneAlso: esmethadone, dextromethadone, REL-1017Patients will take one tablet of 25 mg d-methadone once daily at 6 pm over a period of 30 days | Drug | 25 mg d-methadone |
| PlaceboPatients will take one tablet of placebo once daily at 6 pm over a period of 30 days | Other | Placebo |
Primary outcome
Efficacy of d-methadone
Time frame: 30 days
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.
4 secondary outcomes
Insomnia severity
Time frame: 10 and 30 days
Change in Quality of life
Time frame: 10 and 30 days
Periodic limb movements of sleep index
Time frame: 10 days
Actigrafic parameters
Time frame: 10 and 30 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2026.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mauro Manconi, Prof. MD principal investigator
Ente Ospedaliero Cantonale, Neurocenter of Southern Switzerland
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing D-methadone in people with Restless Legs Syndrome, run by Mauro Manconi at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 13 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Switzerland, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy of d-methadone (time frame: 30 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2026.