<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/NCT03755310</url>
  </required_header>
  <id_info>
    <org_study_id>IISP-57325</org_study_id>
    <nct_id>NCT03755310</nct_id>
  </id_info>
  <brief_title>Treatment of Restless Legs Syndrome With the Hypocretin Antagonist Suvorexant</brief_title>
  <official_title>Proof of Concept Study: Treatment of Restless Legs Syndrome With the Hypocretin Antagonist Suvorexant</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Diego García-Borreguero, MD, PhD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sleep Research Institute (Paseo de la Habana 151, Madrid 28036, SPAIN)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidad Autonoma de Madrid</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Suvorexant improves sleep latency and wake after sleep onset in patients with primary&#xD;
      insomnia, and is FDA approved for this condition.&#xD;
&#xD;
      However, no data exist on its effects in RLS, so far. The investigators consider that&#xD;
      suvorexant might provide a stable therapeutic efficacy for the long treatment, avoiding the&#xD;
      risk of augmentation of symptoms commonly seen under dopamine agonists.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a common neurological disorder&#xD;
      characterized by the presence of an urge to move the legs, usually accompanied by&#xD;
      dysesthesias1. It is estimated that approx. 60-75% of the patients experience these symptoms&#xD;
      just at bedtime and its main consequence is insomnia. RLS is not only a common differential&#xD;
      diagnosis with Primary Insomnia, but independently of this it is also one of the most common&#xD;
      sleep disorders. In Western countries the prevalence for the more severe forms is&#xD;
      approximately 2-3% of the general adult population.&#xD;
&#xD;
      Over the last years, dopamine agonists (DAs) have been widely used for RLS/WED. However,&#xD;
      there is growing concern about the long-term consequences of DAs, such as dopaminergic&#xD;
      augmentation. This complication consists of an overall increase in symptom severity, with&#xD;
      symptoms starting earlier in the afternoon and expanding to previously unaffected parts of&#xD;
      the body. If not stopped, augmentation can develop into a serious complication, as it will&#xD;
      eventually progress and can lead to discontinuation of treatment. Existing studies show that&#xD;
      after a treatment period of approximately 10 years, which is the amount of time that has&#xD;
      elapsed since the first DA agonists were approved, the prevalence of augmentation nears 50%.&#xD;
      But since RLS is a chronic disease in many patients, it is likely that with longer treatment&#xD;
      times the risk of augmentation will increase even further. In light of this, there is a&#xD;
      clinical need for treatment alternatives to dopaminergic drugs. Furthermore, a recent&#xD;
      consensus paper by three RLS expert organizations recommends treatment begin with drugs other&#xD;
      than dopaminergic agonists.&#xD;
&#xD;
      The pathophysiology of RLS/WED is not yet clear, but a number of findings link it to iron&#xD;
      metabolism and to a mild dopaminergic dysfunction. Furthermore, it is not even clear whether&#xD;
      the dopaminergic dysfunction plays a causal role at all, a fact that adds additional concerns&#xD;
      about the use of dopaminergics. Drugs with non-dopaminergic mechanisms of action that have&#xD;
      shown therapeutic efficacy for RLS/WED are alpha-2 delta ligands (pregabalin, gabapentin),&#xD;
      opiates, benzodiazepines or clonidine. The only common mechanism through which these&#xD;
      different agents might improve RLS symptoms is probably reduction of arousal. In fact, RLS&#xD;
      even when moderate profoundly disturbs sleep, reducing sleep times to 5-6 hours or less.&#xD;
      Patients report some daytime problems with alertness and cognitive clarity, but despite this&#xD;
      reduction in sleep times untreated patients do not describe such profound episodes of&#xD;
      sleepiness that occur for normal subjects maintained on such restricted sleep schedules.&#xD;
      There is apparently some alerting mechanism partially compensating for the sleep loss.&#xD;
      Such-hyperarousal-resembles the one found in Primary Insomnia. Indeed, RLS patients treated&#xD;
      with dopaminergics over long periods frequently exhibit poor sleep despite the improvement of&#xD;
      sensory and motor symptoms.&#xD;
&#xD;
      Increased glutamatergic activity has been discussed as one of the potential mechanisms&#xD;
      leading to increased arousal in RLS. However, it is possible that the hypocretin system may&#xD;
      also play a role in causing RLS-related hyperarousal. Hypocretins are well known to play a&#xD;
      key role in the central regulation of both motor control and arousal. Two main studies have&#xD;
      examined hypocretin levels in RLS patients. A first small study found increased evening&#xD;
      hypocretin-1 levels in previously untreated patients with early onset RLS when compared to&#xD;
      controls, but not in those treated. However, Stiasny-Kolster et al. were not able to&#xD;
      replicate this finding, although the difference between both studies could be related to the&#xD;
      treatment status and to the use of different extraction methods of cerebrospinal fluid (CSF).&#xD;
      No evidence exists so far in the literature regarding the effect of hypocretin antagonist&#xD;
      drugs in the treatment of RLS-related sensory and motor symptoms. However, unpublished data&#xD;
      have shown non-significant improvements of periodic limb movements (PLMs) during treatment&#xD;
      with almorexant.&#xD;
&#xD;
      This study hypothesizes that treatment of RLS symptoms with the hypocretin antagonist&#xD;
      suvorexant might lead to an improvement of sleep as well as to an improvement of both&#xD;
      dysesthesias and motor symptoms (PLMs).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 2019</start_date>
  <completion_date type="Anticipated">March 2020</completion_date>
  <primary_completion_date type="Anticipated">March 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change (differences between visits 2 and 5) in Wake Time After Sleep Onset (WASO), as measured during polysomnography</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in International Restless Legs Scale (IRLS)</measure>
    <time_frame>1 year</time_frame>
    <description>IRLS is the main scale for rating the severity of restless legs syndrome. Scoring criteria: Mild (score 1-10); Moderate (score 11-20); Severe (score 21-30); Very severe (score 31-40)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in Clinical Global Impressions (CGI)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in Total Sleep Time (TST)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in Periodic Leg Movement during Sleep-index (PLMS)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in Periodic Leg movement while awake-index (PLMW-index)</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change (differences between visits 2 and 5) in Multiple Suggested Immobilization Test (mSIT).</measure>
    <time_frame>1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">43</enrollment>
  <condition>Restless Legs Syndrome</condition>
  <arm_group>
    <arm_group_label>Suvorexant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10mg tabs during the first week, 10-20 mg tabs on the second week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Equivalent dosage, route of administration and dose regimen.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Suvorexant</intervention_name>
    <description>First week: 10 mg tabs; Second week: 10-20 mg tabs</description>
    <arm_group_label>Suvorexant</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Equivalent dosage, route of administration and dose regimen</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Idiopathic RLS, according to diagnostic criteria established by the International RLS&#xD;
             Study Group (Allen et al., 2003).&#xD;
&#xD;
          -  A history (if currently controlled on medication) or the presence of RLS symptoms&#xD;
             causing insomnia/ sleep disturbance on 3 or more days per week for at least 12 months.&#xD;
&#xD;
          -  Both treatment-naïve and treated patients without a sufficient response will be&#xD;
             included. In both of these groups, the IRLS score ≥20 at the screening assessment (for&#xD;
             the latter group, measured under current treatment), with an absence of significant&#xD;
             RLS symptoms before 9PM (measured by diary)&#xD;
&#xD;
          -  Aged 18 - 80 years.&#xD;
&#xD;
          -  PSG at baseline containing:&#xD;
&#xD;
               -  WASO≥ 60 minutes&#xD;
&#xD;
               -  PLMAI of ≥ 15&#xD;
&#xD;
               -  TST&lt;6.6hours&#xD;
&#xD;
          -  Women of childbearing potential must have a negative pregnancy test at screen and must&#xD;
             agree not to become pregnant.&#xD;
&#xD;
          -  Prior to any study-specific procedures, a personally signed and dated informed consent&#xD;
             document indicating that the patient has been informed of all pertinent aspects of the&#xD;
             trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any secondary forms of RLS.&#xD;
&#xD;
          -  History or current diagnosis of other clinically relevant diseases that may confound&#xD;
             assessments or RLS symptoms.&#xD;
&#xD;
          -  Serum ferritin &lt;18 mcg/ml&#xD;
&#xD;
          -  If the patient is currently being treated with drugs likely to influence sleep&#xD;
             architecture or motor manifestations during sleep (such as neuroleptics, L-dopa,&#xD;
             dopamine agonists, hypnotics, sedatives, antidepressants, anxiolytics,&#xD;
             anticonvulsants, psychostimulant medications, steroids, barbiturates and opiates), a&#xD;
             wash-out period of at least &gt; 5 half-lives will be undertaken.&#xD;
&#xD;
          -  Employed in shift work (for example, employment hours disruptive to the normal&#xD;
             circadian sleep-wake cycle such as nighttime or variable rotating shifts) or irregular&#xD;
             sleep-wake schedules.&#xD;
&#xD;
          -  Patients who require prescription medication for concurrent conditions which could&#xD;
             interfere with efficacy assessments such as dopamine antagonists, serotonin reuptake&#xD;
             inhibitors or antihistamines.&#xD;
&#xD;
          -  Surgery within 180 days of baseline visit, which in the opinion of the investigator&#xD;
             would negatively impact the patient's participation in the study.&#xD;
&#xD;
          -  A significant medical or psychiatric disorder.&#xD;
&#xD;
          -  Any other clinically significant condition or laboratory assay abnormality, which&#xD;
             would interfere with the patient's ability to participate in the study.&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition or laboratory assay&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration or may interfere with the interpretation of study results and&#xD;
             would make the patient inappropriate for entry into this study.&#xD;
&#xD;
          -  Pregnancy and breastfeeding.&#xD;
&#xD;
          -  Any disorders for which suvorexant is contraindicated, such as: narcolepsy, COPD,&#xD;
             sleep apnea, depression, suicidal thoughts, severe hepatic illness.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Diego García-Borreguero, MD. PhD.</last_name>
    <phone>+34 913 454 129</phone>
    <email>dgb@iis.es</email>
  </overall_contact>
  <location>
    <facility>
      <name>Sleep Research Institute; Paseo de la Habana 151</name>
      <address>
        <city>Madrid</city>
        <zip>28036</zip>
        <country>Spain</country>
      </address>
    </facility>
    <contact>
      <last_name>Diego García-Berreguero</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>1. Sleep Med 2014;15(8):860-73. 2. Sleep Med. 2013;14(7):675-84. 3. Sleep Med 2012;13:1280-5. 4. Sleep Med 2011;12:440-4. 5. Sleep Med 2015;16(10):1252-8. 6. Sleep Med. 2016;21:1-11. 7. Sleep Med Clin 2015;10:207-14, xi. 8. Sleep Med. 2009;10(1):134-8. 9. Neurology. 2013;80(22):2028-34 10. Neurosci Biobehav Rev. 2015;49:43-54. 11. Peptides. 2014;52:29-37. 12. Curr Biol. 2013;23(18):1719-25. 13. Curr Opin Neurobiol. 2013;23(5):752-9. 14. Neurosci Bull. 2013;29(3):355-65. 15. Neurology. 2002;59(4):639-</citation>
  </reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>August 10, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 27, 2018</study_first_posted>
  <last_update_submitted>November 27, 2018</last_update_submitted>
  <last_update_submitted_qc>November 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 29, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Universidad Autonoma de Madrid</investigator_affiliation>
    <investigator_full_name>Diego García-Borreguero, MD, PhD</investigator_full_name>
    <investigator_title>Sleep Research Institute</investigator_title>
  </responsible_party>
  <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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Suvorexant</mesh_term>
  </intervention_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/NCT03755310
org study id: IISP-57325
nct id: NCT03755310
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Suvorexant improves sleep latency and wake after sleep onset in patients with primary
      insomnia, and is FDA approved for this condition.

      However, no data exist on its effects in RLS, so far. The investigators consider that
      suvorexant might provide a stable therapeutic efficacy for the long treatment, avoiding the
      risk of augmentation of symptoms commonly seen under dopamine agonists.
Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a common neurological disorder
      characterized by the presence of an urge to move the legs, usually accompanied by
      dysesthesias1. It is estimated that approx. 60-75% of the patients experience these symptoms
      just at bedtime and its main consequence is insomnia. RLS is not only a common differential
      diagnosis with Primary Insomnia, but independently of this it is also one of the most common
      sleep disorders. In Western countries the prevalence for the more severe forms is
      approximately 2-3% of the general adult population.

      Over the last years, dopamine agonists (DAs) have been widely used for RLS/WED. However,
      there is growing concern about the long-term consequences of DAs, such as dopaminergic
      augmentation. This complication consists of an overall increase in symptom severity, with
      symptoms starting earlier in the afternoon and expanding to previously unaffected parts of
      the body. If not stopped, augmentation can develop into a serious complication, as it will
      eventually progress and can lead to discontinuation of treatment. Existing studies show that
      after a treatment period of approximately 10 years, which is the amount of time that has
      elapsed since the first DA agonists were approved, the prevalence of augmentation nears 50%.
      But since RLS is a chronic disease in many patients, it is likely that with longer treatment
      times the risk of augmentation will increase even further. In light of this, there is a
      clinical need for treatment alternatives to dopaminergic drugs. Furthermore, a recent
      consensus paper by three RLS expert organizations recommends treatment begin with drugs other
      than dopaminergic agonists.

      The pathophysiology of RLS/WED is not yet clear, but a number of findings link it to iron
      metabolism and to a mild dopaminergic dysfunction. Furthermore, it is not even clear whether
      the dopaminergic dysfunction plays a causal role at all, a fact that adds additional concerns
      about the use of dopaminergics. Drugs with non-dopaminergic mechanisms of action that have
      shown therapeutic efficacy for RLS/WED are alpha-2 delta ligands (pregabalin, gabapentin),
      opiates, benzodiazepines or clonidine. The only common mechanism through which these
      different agents might improve RLS symptoms is probably reduction of arousal. In fact, RLS
      even when moderate profoundly disturbs sleep, reducing sleep times to 5-6 hours or less.
      Patients report some daytime problems with alertness and cognitive clarity, but despite this
      reduction in sleep times untreated patients do not describe such profound episodes of
      sleepiness that occur for normal subjects maintained on such restricted sleep schedules.
      There is apparently some alerting mechanism partially compensating for the sleep loss.
      Such-hyperarousal-resembles the one found in Primary Insomnia. Indeed, RLS patients treated
      with dopaminergics over long periods frequently exhibit poor sleep despite the improvement of
      sensory and motor symptoms.

      Increased glutamatergic activity has been discussed as one of the potential mechanisms
      leading to increased arousal in RLS. However, it is possible that the hypocretin system may
      also play a role in causing RLS-related hyperarousal. Hypocretins are well known to play a
      key role in the central regulation of both motor control and arousal. Two main studies have
      examined hypocretin levels in RLS patients. A first small study found increased evening
      hypocretin-1 levels in previously untreated patients with early onset RLS when compared to
      controls, but not in those treated. However, Stiasny-Kolster et al. were not able to
      replicate this finding, although the difference between both studies could be related to the
      treatment status and to the use of different extraction methods of cerebrospinal fluid (CSF).
      No evidence exists so far in the literature regarding the effect of hypocretin antagonist
      drugs in the treatment of RLS-related sensory and motor symptoms. However, unpublished data
      have shown non-significant improvements of periodic limb movements (PLMs) during treatment
      with almorexant.

      This study hypothesizes that treatment of RLS symptoms with the hypocretin antagonist
      suvorexant might lead to an improvement of sleep as well as to an improvement of both
      dysesthesias and motor symptoms (PLMs).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change (differences between visits 2 and 5) in Wake Time After Sleep Onset (WASO), as measured during polysomnography
time frame: 1 year
measure: Change (differences between visits 2 and 5) in International Restless Legs Scale (IRLS)
time frame: 1 year
description: IRLS is the main scale for rating the severity of restless legs syndrome. Scoring criteria: Mild (score 1-10); Moderate (score 11-20); Severe (score 21-30); Very severe (score 31-40)
measure: Change (differences between visits 2 and 5) in Clinical Global Impressions (CGI)
time frame: 1 year
measure: Change (differences between visits 2 and 5) in Total Sleep Time (TST)
time frame: 1 year
measure: Change (differences between visits 2 and 5) in Periodic Leg Movement during Sleep-index (PLMS)
time frame: 1 year
measure: Change (differences between visits 2 and 5) in Periodic Leg movement while awake-index (PLMW-index)
time frame: 1 year
measure: Change (differences between visits 2 and 5) in Multiple Suggested Immobilization Test (mSIT).
time frame: 1 year
arm group label: Suvorexant
arm group type: Experimental
description: 10mg tabs during the first week, 10-20 mg tabs on the second week.
arm group label: Placebo
arm group type: Placebo Comparator
description: Equivalent dosage, route of administration and dose regimen.
intervention type: Drug
intervention name: Suvorexant
description: First week: 10 mg tabs; Second week: 10-20 mg tabs
arm group label: Suvorexant
intervention type: Drug
intervention name: Placebo
description: Equivalent dosage, route of administration and dose regimen
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Diego García-Borreguero, MD. PhD.
phone: +34 913 454 129
email: dgb@iis.es
facility: 
contact: 
country: Spain
citation: 1. Sleep Med 2014;15(8):860-73. 2. Sleep Med. 2013;14(7):675-84. 3. Sleep Med 2012;13:1280-5. 4. Sleep Med 2011;12:440-4. 5. Sleep Med 2015;16(10):1252-8. 6. Sleep Med. 2016;21:1-11. 7. Sleep Med Clin 2015;10:207-14, xi. 8. Sleep Med. 2009;10(1):134-8. 9. Neurology. 2013;80(22):2028-34 10. Neurosci Biobehav Rev. 2015;49:43-54. 11. Peptides. 2014;52:29-37. 12. Curr Biol. 2013;23(18):1719-25. 13. Curr Opin Neurobiol. 2013;23(5):752-9. 14. Neurosci Bull. 2013;29(3):355-65. 15. Neurology. 2002;59(4):639-
responsible party type: Sponsor-Investigator
investigator affiliation: Universidad Autonoma de Madrid
investigator full name: Diego García-Borreguero, MD, PhD
investigator title: Sleep Research Institute
mesh term: Psychomotor Agitation
mesh term: Restless Legs Syndrome
mesh term: Syndrome
mesh term: Suvorexant