<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01675323</url>
  </required_header>
  <id_info>
    <org_study_id>NA_00073951</org_study_id>
    <nct_id>NCT01675323</nct_id>
  </id_info>
  <brief_title>Glutamate, Hyperarousal and Restless Legs Syndrome</brief_title>
  <official_title>Glutamate, Hyperarousal and Restless Legs Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institutes of Health (NIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Johns Hopkins University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Restless Legs Syndrome (RLS) research has focused on the sensory features and failed to&#xD;
      address an important aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss&#xD;
      without significant excessive daytime sleepiness. This hyperarousal produces RLS symptoms by&#xD;
      overwhelming the normal inhibitory processes needed to decrease sensory and motor cortical&#xD;
      activity for resting and sleep. Thus the hyperarousal produces both the RLS need to move when&#xD;
      trying to rest and the inability to maintain sleep. The biological consequences of this&#xD;
      hyperarousal process on sleep (increased wake time) and cortical excitability (as&#xD;
      demonstrated by transcranial magnetic stimulation (TMS)) are postulated to reflect increased&#xD;
      degree of excitatory glutamatergic activity, and therefore affected brain regions will show&#xD;
      relatively increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in&#xD;
      inhibitory activity and GABA may also occur, but less significantly than the increase in&#xD;
      Glu/Gln. Our pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu&#xD;
      + Gln) that correlated well with sleep measures of hyperarousal. Glx levels are not specific&#xD;
      for the neurotransmitter role of Glu.&#xD;
&#xD;
      In this project RLS and matching controls subjects will be studied using polysomnograms (PSG)&#xD;
      and TMS and 7T MRI for MRS that provides accurate measurement of Gln levels, which reflect&#xD;
      mostly neurotransmitter Glu activity. The first aim is to confirm that Gln is increased in&#xD;
      the thalamus and to determine if this also occurs in the motor and sensory cortices. The&#xD;
      relation between Glu, Gln and GABA will also be evaluated. Second, assessments will be made&#xD;
      of the degree of relation between Gln increase and the hyperarousal effects on sleep and&#xD;
      cortical excitability (TMS). This would demonstrate that abnormally increased Glu activity is&#xD;
      primary to RLS hyperarousal and radically changes the emphasis in RLS to be less on dopamine&#xD;
      and more on Glu-hyperarousal as a major feature of RLS.This is an entirely new direction for&#xD;
      RLS research and treatment development. The new concept of hyperarousal adds a missing&#xD;
      dimension to understanding RLS, namely the discovery of the Glu abnormality and its central&#xD;
      relation to the other hyperarousal features.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Moderate to severe Restless Legs Syndrome (RLS) is a major public health problem,&#xD;
      significantly affecting 1.5 to 3% of adult Americans (3 - 7 million), resulting in profound&#xD;
      sleep loss and an urge to move during sitting or resting in the later part of the day. Work&#xD;
      productivity is decreased by 20%, quality of life is as bad or worse than that for other&#xD;
      chronic diseases, e.g. arthritis and diabetes, and there is increased cardio-vascular disease&#xD;
      risk. Current approved dopaminergic treatments fail to improve sleep time, engender impulsive&#xD;
      behaviors and may make RLS worse. New treatments and new research directions to find them are&#xD;
      needed. The current research focus on the sensory features has failed to address an important&#xD;
      aspect of RLS; i.e. a 'hyperarousal' or profound chronic sleep loss without significant&#xD;
      excessive daytime sleepiness. This hyperarousal produces RLS symptoms by overwhelming the&#xD;
      normal inhibitory processes needed to decrease sensory and motor cortical activity for&#xD;
      resting and sleep. Thus the hyperarousal produces both the RLS need to move when trying to&#xD;
      rest and the inability to maintain sleep. The biological consequences of this hyperarousal&#xD;
      process on sleep (increased wake time) and cortical excitability (as demonstrated by&#xD;
      transcranial magnetic stimulation (TMS)) are postulated to reflect increased degree of&#xD;
      excitatory glutamatergic activity, and therefore affected brain regions will show relatively&#xD;
      increased glutamate (Glu) and glutamine (Gln) on MR spectroscopy (MRS). Changes in inhibitory&#xD;
      activity and GABA may also occur, but less significantly than the increase in Glu/Gln. Our&#xD;
      pilot MRS data discovered a new abnormality in RLS: increased Thalamic Glx (Glu + Gln) that&#xD;
      correlated well with sleep measures of hyperarousal. Glx levels are not specific for the&#xD;
      neurotransmitter role of Glu. In this project RLS and matching controls subjects will be&#xD;
      studied using polysomnograms (PSG) and TMS and 7T MRI for MRS that provides accurate&#xD;
      measurement of Gln levels, which reflect mostly neurotransmitter Glu activity. The first aim&#xD;
      is to confirm that Gln is increased in the thalamus and to determine if this also occurs in&#xD;
      the motor and sensory cortices. The relation between Glu, Gln and GABA will also be&#xD;
      evaluated. Second, assessments will be made of the degree of relation between Gln increase&#xD;
      and the hyperarousal effects on sleep and cortical excitability (TMS). This would demonstrate&#xD;
      that abnormally increased Glu activity is primary to RLS hyperarousal and radically changes&#xD;
      the emphasis in RLS to be less on dopamine and more on Glu-hyperarousal as a major feature of&#xD;
      RLS. This is an entirely new direction for RLS research and treatment development. The new&#xD;
      concept of hyperarousal adds a missing dimension to understanding RLS, namely the discovery&#xD;
      of the Glu abnormality and its central relation to the other hyperarousal features. It opens&#xD;
      the opportunity to develop new animal and cell RLS research. It provides new directions for&#xD;
      medication treatment development, changes the emphasis for primary treatment toward Glu drugs&#xD;
      and the MRS provides a useful and accessible measure for evaluating medication treatment&#xD;
      benefits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>MR Spectroscopy - Glutamate</measure>
    <time_frame>2nd Day of Phase 2</time_frame>
    <description>Study of thalamic glutamate levels in the brain using MR Spectroscopy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>MR Spectroscopy - GABA</measure>
    <time_frame>2nd Day of Phase 2</time_frame>
    <description>Study of thalamic GABA levels in the brain using MR Spectroscopy</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">77</enrollment>
  <condition>Restless Legs Syndrome</condition>
  <arm_group>
    <arm_group_label>RLS Patients</arm_group_label>
    <description>Participants who have diagnosed RLS with diagnosis confirmed by study investigators.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <description>Participants without RLS who are generally healthy and matched for gender, age, educational level, and race to patients in the RLS group.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood and urine (female participants only)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Subjects with RLS and healthy subjects, 18 years of age or older, matched for age, gender,&#xD;
        race, and educational level. Both men and women will be included.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All subjects&#xD;
&#xD;
               1. 18 years or older&#xD;
&#xD;
               2. Normal mental status and able to give informed consent.&#xD;
&#xD;
               3. Regular sleep times start between 21:00 and 01:00 5 out of 7 days a week&#xD;
&#xD;
               4. General good health and ambulatory&#xD;
&#xD;
          -  RLS patients&#xD;
&#xD;
               1. Diagnosis of primary RLS confirmed by the PI or Dr. Earley&#xD;
&#xD;
               2. History indicating if RLS symptoms were not treated, thy would for the last 6&#xD;
                  months&#xD;
&#xD;
                    1. Occur at least 5 out of 7 days a week&#xD;
&#xD;
                    2. Almost always disrupt sleep&#xD;
&#xD;
               3. For phase 2 admission to the Clinical Research Unit: Home screening on a clinical&#xD;
                  log shows RLS symptoms for at least 5 of 7 days, IRLS score at the end of home&#xD;
                  monitoring ≥ 15 and PAM-RL measures show average PLMS/hr ≥15.&#xD;
&#xD;
          -  Control subjects&#xD;
&#xD;
               1. No history of any of the 4 essential criteria for diagnosis of RLS (1).&#xD;
&#xD;
               2. For phase 2 admission to the Clinical Research Unit: Home screening on the PAM-RL&#xD;
                  indicates average PLMS/hr ≤ 10 and the sleep-wake log shows regular times in bed&#xD;
                  between 21:00 and 01:00 bed times with 6.0 to 10.0 hours in bed for 5 out of for&#xD;
                  7 nights.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  All subjects&#xD;
&#xD;
               1. Major mental history as determined by history&#xD;
&#xD;
               2. Clinically significant sleep apnea on prior PSG or on screening first night PSG&#xD;
                  (apnea/hypopnea rate &gt;15/hr).&#xD;
&#xD;
               3. Any medical or neurological disorder other than RLS likely to compromise normal&#xD;
                  sleep, interfere with interpretation of results, or would place the subject at&#xD;
                  risk when participating in the study (e.g. Chronic pain, dementia, ALS, stroke,&#xD;
                  MS, untreated thyroid).&#xD;
&#xD;
               4. Any use of DA antagonists for more than one week in the past 6 months, other than&#xD;
                  for nausea.&#xD;
&#xD;
               5. Women who are pregnant or lactating or at risk for getting pregnant (not using&#xD;
                  appropriate birth control nor post-menopausal).&#xD;
&#xD;
               6. Failure to have clear hand dominance, ambidextrous as assessed by the Edinburgh&#xD;
                  Handedness Inventory (Could influence outcomes on TMS).&#xD;
&#xD;
               7. Musicians and professional typists (Might influence performance on TMS measure)&#xD;
&#xD;
               8. A significant neurological disorder (such as stroke, Parkinson's Disorder,&#xD;
                  Multiple Sclerosis) that could impair fine motor performance.&#xD;
&#xD;
               9. Metal in the body (e.g., pacemakers, implantable pumps, stimulators,&#xD;
                  orthodontics, etc) that would cause problems for the MRI or TMS.&#xD;
&#xD;
              10. Medication use that would alter sleep including any GABA active medications and&#xD;
                  any anti- depressants or other significant psychiatric medications or medications&#xD;
                  that would affect Glu.&#xD;
&#xD;
              11. History of claustrophobia or problems with closed MRI scans not resolved.&#xD;
&#xD;
              12. History of vertigo, seizure disorder, middle-ear disorder, or double vision.&#xD;
&#xD;
              13. Body size not compatible with using T7 MRI.&#xD;
&#xD;
          -  RLS patients&#xD;
&#xD;
               1. History of clinically significant sleep disorder other than that with RLS.&#xD;
&#xD;
               2. Medical disorder or current medication use that exacerbates or might have started&#xD;
                  the RLS&#xD;
&#xD;
          -  Control subjects&#xD;
&#xD;
               1. History of clinically significant sleep disorder including insomnia (primary or&#xD;
                  psycho-physiological)&#xD;
&#xD;
               2. Score on the Pittsburgh Sleep Quality Inventory (PSQI) &gt;5&#xD;
&#xD;
               3. Family history indicating possible RLS in a first-degree relative&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Richard Allen, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Baview Medical</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Bayview Medical Campus</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>August 27, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2012</study_first_posted>
  <last_update_submitted>February 28, 2017</last_update_submitted>
  <last_update_submitted_qc>February 28, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Johns Hopkins University</investigator_affiliation>
    <investigator_full_name>Richard Allen</investigator_full_name>
    <investigator_title>Research Associate, Department of Neurology</investigator_title>
  </responsible_party>
  <keyword>Restless Legs Syndrome</keyword>
  <keyword>RLS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Psychomotor Agitation</mesh_term>
    <mesh_term>Restless Legs Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01675323
org study id: NA_00073951
nct id: NCT01675323
lead sponsor: 
collaborator: 
has dmc: No
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.
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.
observational model: Case-Control
time perspective: Prospective
measure: MR Spectroscopy - Glutamate
time frame: 2nd Day of Phase 2
description: Study of thalamic glutamate levels in the brain using MR Spectroscopy
measure: MR Spectroscopy - GABA
time frame: 2nd Day of Phase 2
description: Study of thalamic GABA levels in the brain using MR Spectroscopy
arm group label: RLS Patients
description: Participants who have diagnosed RLS with diagnosis confirmed by study investigators.
arm group label: Healthy Controls
description: Participants without RLS who are generally healthy and matched for gender, age, educational level, and race to patients in the RLS group.
Whole blood and urine (female participants only)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Richard Allen, Ph.D.
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Johns Hopkins University
investigator full name: Richard Allen
investigator title: Research Associate, Department of Neurology
mesh term: Psychomotor Agitation
mesh term: Restless Legs Syndrome
mesh term: Syndrome