Restless Legs SyndromeNCT01675323
Glutamate, Hyperarousal and Restless Legs Syndrome
An observational study of Restless Legs Syndrome, run by Johns Hopkins University at 2 sites in United States.
Trial summary
Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Restless Legs Syndrome
- How many people
- 77 participants
- Where
- 2 sitesUnited States
- Study dates
- Aug 2012to Jul 2016
- Phase
- Observational
- 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 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Subjects with RLS and healthy subjects, 18 years of age or older, matched for age, gender, race, and educational level. Both men and women will be included.
Who may be able to join
- All subjects
- 18 years or older
- Normal mental status and able to give informed consent.
- Regular sleep times start between 21:00 and 01:00 5 out of 7 days a week
- General good health and ambulatory
- RLS patients
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- Diagnosis of primary RLS confirmed by the PI or Dr. Earley
- History indicating if RLS symptoms were not treated, thy would for the last 6 months
- Occur at least 5 out of 7 days a week
- Almost always disrupt sleep
- For phase 2 admission to the Clinical Research Unit: Home screening on a clinical log shows RLS symptoms for at least 5 of 7 days, IRLS score at the end of home monitoring ≥ 15 and PAM-RL measures show average PLMS/hr ≥15.
- Control subjects
- No history of any of the 4 essential criteria for diagnosis of RLS (1).
- For phase 2 admission to the Clinical Research Unit: Home screening on the PAM-RL indicates average PLMS/hr ≤ 10 and the sleep-wake log shows regular times in bed between 21:00 and 01:00 bed times with 6.0 to 10.0 hours in bed for 5 out of for 7 nights.
Who cannot join
- All subjects
- Major mental history as determined by history
- Clinically significant sleep apnea on prior PSG or on screening first night PSG (apnea/hypopnea rate >15/hr).
- Any medical or neurological disorder other than RLS likely to compromise normal sleep, interfere with interpretation of results, or would place the subject at risk when participating in the study (e.g. Chronic pain, dementia, ALS, stroke, MS, untreated thyroid).
- Any use of DA antagonists for more than one week in the past 6 months, other than for nausea.
- Women who are pregnant or lactating or at risk for getting pregnant (not using appropriate birth control nor post-menopausal).
Show all 21Show fewer
- Failure to have clear hand dominance, ambidextrous as assessed by the Edinburgh Handedness Inventory (Could influence outcomes on TMS).
- Musicians and professional typists (Might influence performance on TMS measure)
- A significant neurological disorder (such as stroke, Parkinson's Disorder, Multiple Sclerosis) that could impair fine motor performance.
- Metal in the body (e.g., pacemakers, implantable pumps, stimulators, orthodontics, etc) that would cause problems for the MRI or TMS.
- Medication use that would alter sleep including any GABA active medications and any anti- depressants or other significant psychiatric medications or medications that would affect Glu.
- History of claustrophobia or problems with closed MRI scans not resolved.
- History of vertigo, seizure disorder, middle-ear disorder, or double vision.
- Body size not compatible with using T7 MRI.
- RLS patients
- History of clinically significant sleep disorder other than that with RLS.
- Medical disorder or current medication use that exacerbates or might have started the RLS
- Control subjects
- History of clinically significant sleep disorder including insomnia (primary or psycho-physiological)
- Score on the Pittsburgh Sleep Quality Inventory (PSQI) >5
- Family history indicating possible RLS in a first-degree relative
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Johns Hopkins Baview Medical
Baltimore, Maryland, 21224
Johns Hopkins Bayview Medical Campus
Baltimore, Maryland, 21224
About this study
Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu.
In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of RLS.This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features.
Read the detailed description
Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound sleep loss and an urge to move during sitting or resting in the later part of the day. Work productivity is decreased by 20%, quality of life is as bad or worse than that for other chronic diseases, e.g. arthritis and diabetes, and there is increased cardio-vascular disease risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive behaviors and may make RLS worse. New treatments and new research directions to find them are needed. The current research focus on the sensory features has failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of RLS. This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features. It opens the opportunity to develop new animal and cell RLS research. It provides new directions for medication treatment development, changes the emphasis for primary treatment toward Glu drugs and the MRS provides a useful and accessible measure for evaluating medication treatment benefits.
- Conditions
- Restless Legs Syndrome
- Keywords
- Restless Legs Syndrome, RLS
- 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.
| Study group | Role | What they receive |
|---|---|---|
| RLS Patients | Participants who have diagnosed RLS with diagnosis confirmed by study investigators. | |
| Healthy Controls | Participants without RLS who are generally healthy and matched for gender, age, educational level, and race to patients in the RLS group. |
What is being measured
The primary outcome is the main question the study is designed to answer.
MR Spectroscopy - Glutamate
Study of thalamic glutamate levels in the brain using MR Spectroscopy
Measured: 2nd Day of Phase 2
MR Spectroscopy - GABA
Study of thalamic GABA levels in the brain using MR Spectroscopy
Measured: 2nd Day of Phase 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Aug 2012 (estimated)
- Study startAug 2012
- Primary completionJul 2016
- Study completionJul 2016
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.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- 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
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 77 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Responsible party
- Principal investigator, Richard Allen, Johns Hopkins University
- Investigators
- Richard Allen, Ph.D., Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01675323
- Sponsor's protocol ID
- NA_00073951
- Status last verified
- Feb 2017
- First submitted
- 27 Aug 2012
- Last updated
- 1 Mar 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Glutamate, Hyperarousal and Restless Legs Syndrome
- ClinicalTrials.gov ID
- NCT01675323
- Acronym / sponsor ID
- NA_00073951
- Conditions
- Restless Legs Syndrome
- Keywords
- Restless Legs Syndrome, RLS
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 77 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Study start
- Aug 2012
- Primary completion
- Jul 2016 (actual)
- Study completion
- Jul 2016 (actual)
- First posted
- 29 Aug 2012 (estimated)
- 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.
Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu.
In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of RLS.This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features.
Detailed description
Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem, significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound sleep loss and an urge to move during sitting or resting in the later part of the day. Work productivity is decreased by 20%, quality of life is as bad or worse than that for other chronic diseases, e.g. arthritis and diabetes, and there is increased cardio-vascular disease risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive behaviors and may make RLS worse. New treatments and new research directions to find them are needed. The current research focus on the sensory features has failed to address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to rest and the inability to maintain sleep. The biological consequences of this hyperarousal process on sleep (increased wake time) and cortical excitability (as demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of excitatory glutamatergic activity, and therefore affected brain regions will show relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific for the neurotransmitter role of Glu. In this project RLS and matching controls subjects will be studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in the thalamus and to determine if this also occurs in the motor and sensory cortices. The relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made of the degree of relation between Gln increase and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of RLS. This is an entirely new direction for RLS research and treatment development. The new concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery of the Glu abnormality and its central relation to the other hyperarousal features. It opens the opportunity to develop new animal and cell RLS research. It provides new directions for medication treatment development, changes the emphasis for primary treatment toward Glu drugs and the MRS provides a useful and accessible measure for evaluating medication treatment benefits.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| RLS Patients | – | –Participants who have diagnosed RLS with diagnosis confirmed by study investigators. |
| Healthy Controls | – | –Participants without RLS who are generally healthy and matched for gender, age, educational level, and race to patients in the RLS group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Subjects with RLS and healthy subjects, 18 years of age or older, matched for age, gender, race, and educational level. Both men and women will be included.
Key inclusion criteria (14 listed)
- All subjects
- RLS patients
- Control subjects
Key exclusion criteria (21 listed)
- All subjects
- RLS patients
- Control subjects
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
MR Spectroscopy - Glutamate
Time frame: 2nd Day of Phase 2
Study of thalamic glutamate levels in the brain using MR Spectroscopy
MR Spectroscopy - GABA
Time frame: 2nd Day of Phase 2
Study of thalamic GABA levels in the brain using MR Spectroscopy
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Mar 2017.
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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.
Richard Allen, Ph.D. principal investigator
Johns Hopkins University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Restless Legs Syndrome, run by Johns Hopkins University at 2 sites in United States.
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 14 inclusion and 21 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: finished, as of the sponsor's last update on 1 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
MR Spectroscopy - Glutamate (time frame: 2nd Day of Phase 2). The study lists 2 primary outcomes in all. 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 1 Mar 2017.