<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/NCT03787238</url>
  </required_header>
  <id_info>
    <org_study_id>GM-18</org_study_id>
    <nct_id>NCT03787238</nct_id>
  </id_info>
  <brief_title>A Randomized, Multicenter, Study for the prEvention and Acute Treatment of Migraine (REAL)</brief_title>
  <acronym>REAL</acronym>
  <official_title>GM-18 - A Randomized, Multicenter, Study for the prEvention and Acute Treatment of Migraine Using Open Label Non-invasive Vagal Nerve Stimulation, Versus Standard of Care (REAL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ElectroCore INC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>ElectroCore INC</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized study for the prevention and acute treatment of migraine using open&#xD;
      label nVNS and standard of care versus standard of care.&#xD;
&#xD;
      .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A randomized study for the prevention and acute treatment of migraine using open label nVNS&#xD;
      and standard of care versus standard of care.&#xD;
&#xD;
      Eligible subjects will participate in a 4 week run-in period after which they will be&#xD;
      randomized (1:1) to either nVNS and standard of care (nVNS group) or standard of care (SOC&#xD;
      group) for 12 weeks. The nVNS group will use the nVNS device preventatively and acutely for&#xD;
      the treatment of migraine. The SOC group will continue to use their regular standard of care&#xD;
      migraine treatment medications for the duration of the 12 week randomized period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Company decision&#xD;
  </why_stopped>
  <start_date type="Anticipated">May 15, 2019</start_date>
  <completion_date type="Anticipated">October 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction in number of migraine days during the last four weeks in the twelve-week randomized period compared with the four-week run-in period</measure>
    <time_frame>The last four weeks in the randomization period compared to the four week run-in period.</time_frame>
    <description>Reduction in number of migraine days during the last four weeks in the twelve-week randomized period compared with the four-week run-in period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Reduction in number of headache days during the last four-weeks in the twelve-week randomized period compared to the four-week run-in period</measure>
    <time_frame>The last four weeks in the randomization period compared to the four week run-in period.</time_frame>
    <description>Reduction in number of headache days during the last four-weeks in the twelve-week randomized period compared to the four-week run-in period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reduction in number of migraine days and headache days (separately)</measure>
    <time_frame>12 week randomised period</time_frame>
    <description>Reduction in number of migraine days and headache days (separately) during weeks 1 through 4, 5 through 8 in the 12 week randomised period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of responders for the nVNS group compared to the standard of care group.</measure>
    <time_frame>The last four weeks in the randomization period compared to the four week run-in period.</time_frame>
    <description>Rate of responders (mean reduction in migraine days during the last four weeks in the twelve-week randomization period compared to the four-week run-in period dichotomized as &lt;25% vs. ≥25%, &lt;50% vs ≥50% and &lt;75% vs ≥75%, separately) for the nVNS group compared to the standard of care group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute treatment response for nVNS and standard of care therapies</measure>
    <time_frame>12 week randomised period</time_frame>
    <description>Acute treatment response for nVNS and standard of care therapies at 30, 60 and 120 minutes post-treatment, for all treated migraine attacks in the twelve-week randomized period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Consistency of response</measure>
    <time_frame>12 week randomised period</time_frame>
    <description>Consistency of response as defined as the percentage of subjects who achieve treatment response in 25%, 50% and 75% or greater of their attacks, in subjects treating at least two attacks, for nVNS and standard of care therapies for all treated migraine attacks during the randomized period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of nVNS as measured by adverse events</measure>
    <time_frame>12 week randomised period</time_frame>
    <description>Safety and tolerability of nVNS as measured by adverse events</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in acute headache medication use</measure>
    <time_frame>12 week randomization period compared to the four week run-in period</time_frame>
    <description>Change in acute headache medication use (proportion of attacks with acute medication use prior to or at 120 minutes post-treatment) for all treated attacks in the twelve-week randomized period compared to the four week run-in period in the nVNS group</description>
  </other_outcome>
  <other_outcome>
    <measure>Presence or absence of nausea, vomiting, photophobia, phonophobia</measure>
    <time_frame>12 week randomised period</time_frame>
    <description>Presence or absence of nausea, vomiting, photophobia, phonophobia at 0, 30, 60 and 120 minutes post treatment for nVNS and standard of care therapies for all treated migraine attacks in the randomized period</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Migraine</condition>
  <arm_group>
    <arm_group_label>non-invasive Vagus Nerve Stimulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>nVNS (non-invasive vagus nerve stimulation) treatment with the gammaCore Sapphire device and standard of care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of Care treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>non-invasive vagus nerve stimulation</intervention_name>
    <description>non-invasive vagus nerve stimulation using the gammaCore Sapphire device</description>
    <arm_group_label>non-invasive Vagus Nerve Stimulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Is 18 years of age or above.&#xD;
&#xD;
          -  Has been previously diagnosed with episodic or chronic migraine (with or without aura)&#xD;
             in accordance with the ICHD-3 Classification criteria.&#xD;
&#xD;
          -  Experience at least 6 and no more than 24 headache days per month and a minimum of 4&#xD;
             migraine attacks per month (over the last 3 months).&#xD;
&#xD;
          -  Has age of onset of migraine less than 50 years old.&#xD;
&#xD;
          -  Stable regime for any migraine preventative medications for the last 3 months and&#xD;
             agrees to maintain stable regime for duration of the study.&#xD;
&#xD;
          -  Agrees to and in clinician opinion is able to use the nVNS device as intended, follow&#xD;
             all of the requirements of the study including follow-up visit requirements, record&#xD;
             required study data in the subject dairy, and other self-assessment questionnaires.&#xD;
&#xD;
          -  Availability of internet/Web access for Web-based e-diary completion&#xD;
&#xD;
          -  Is able to provide written Informed Consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Requires use of oral or injectable steroids for concomitant medical condition that in&#xD;
             the opinion of the investigator will interfere with the study.&#xD;
&#xD;
          -  Has a history of any intracranial aneurysm, intracranial haemorrhage, brain tumour or&#xD;
             significant head trauma.&#xD;
&#xD;
          -  Has a structural abnormality at the nVNS treatment site (e.g. lymphadenopathy previous&#xD;
             surgery or abnormal anatomy).&#xD;
&#xD;
          -  Has pain at the nVNS treatment site (e.g. dysesthesia, neuralgia and/or cervicalgia).&#xD;
&#xD;
          -  Has other significant pain problem (e.g. cancer pain or other head or facial disorder)&#xD;
             that in the opinion of the investigator may confound the study assessments&#xD;
&#xD;
          -  Has known or suspected severe cardiac disease (e.g. symptomatic coronay artery&#xD;
             disease, prior myocardial infarction, congestive heart failure (CHF)).&#xD;
&#xD;
          -  Has known or suspected severe cerebrovascular disease, (e.g. prior stroke or transient&#xD;
             ischemic attack, symptomatic carotid artery disease, prior cartoid endarterectomy or&#xD;
             other vascular neck surgery).&#xD;
&#xD;
          -  Has known or suspected own and/or family history of cardiac disease (including but not&#xD;
             limited to ischemic heart disease, rhythm disturbances, congenital abnormalities&#xD;
             cardiac myopathies), or presents risk factors strongly associated with risk for&#xD;
             developing cardiologic abnormalities that in the opinion of the investigator might&#xD;
             compromise subjects safety using n-VNS.&#xD;
&#xD;
          -  Has had a cervical vagotomy.&#xD;
&#xD;
          -  Has uncontrolled high blood pressure (systolic &gt;160 diastolic &gt; 100 after 3 repeated&#xD;
             measurements within 24 hours).&#xD;
&#xD;
          -  Is currently implanted with an electrical and/or neurostimulator device (e.g. cardiac&#xD;
             pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal&#xD;
             stimulator, bone growth stimulator, cochlear implant, Spehnopalatine ganglion&#xD;
             stimulator or Occiptial nerve stimulator).&#xD;
&#xD;
          -  Has been implanted with metal cervical spine hardware or has a metallic implant near&#xD;
             the nVNS stimulation site (e.g. in the head, neck of thorax).&#xD;
&#xD;
          -  Presents a suspicion of secondary headache.&#xD;
&#xD;
          -  Previous diagnosis of medication overuse headache within the last 3 months&#xD;
&#xD;
          -  Has a history of syncope (within the last 1 year).&#xD;
&#xD;
          -  Has a history of seizures (within the last 1 year).&#xD;
&#xD;
          -  Has a known or suspicion of substance abuse or addiction (within the last 1 year).&#xD;
&#xD;
          -  Has initiated medications for migraine prophylaxis in the previous 30 days, or in the&#xD;
             case of Botulinum toxin and monoclonal antibodies against CGRP injections in the&#xD;
             previous 90 days.&#xD;
&#xD;
          -  Has failed an adequate trial (two months or greater) of at least 3 classes of a drug&#xD;
             therapy for the prophylaxis of migraine.&#xD;
&#xD;
          -  Is pregnant or of childbearing years and is unwilling to use and accepted form of&#xD;
             birth control (condom or contraceptive pill).&#xD;
&#xD;
          -  Is participating in any other therapeutic clinical investigation or has participated&#xD;
             in a clinical trial in the preceding 30 days.&#xD;
&#xD;
          -  Belongs to a vulnerable population or has any condition such that his or her ability&#xD;
             to provide informed consent, comply with the follow-up requirements, or provide self-&#xD;
             assessments is compromised (e.g. homeless, developmentally disabled and prisoner).&#xD;
&#xD;
          -  Has previously used the gammaCore device within the last 3 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alexandra Sinclair, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Birmingham</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Danish Headache Center</name>
      <address>
        <city>Glostrup</city>
        <zip>DK-2600</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CTC, University Medical Center Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>D-20251</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Migräne- und Kopfschmerzklinik Königstein</name>
      <address>
        <city>Königstein im Taunus</city>
        <zip>D-61462</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik für Neurologie, Ludwig-Maximilliams-Universität, Klinikum Grosshadern</name>
      <address>
        <city>München</city>
        <zip>D-81377</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik und Poliklinik für Neurologie, Universitätsmedizin Rostock</name>
      <address>
        <city>Rostock</city>
        <zip>D-18147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Neurological Institute C. Mondino Foundatio</name>
      <address>
        <city>Mondino</city>
        <state>Pavia</state>
        <zip>27100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>U.O. Neurologia III - Cefalee e Neuroalgologia, Fondazione IRCCS Istituto</name>
      <address>
        <city>Milan</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Neurological, Motor and Sensorial Sciences, IRCCS San Raffaele</name>
      <address>
        <city>Rome</city>
        <zip>00163</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Turin</name>
      <address>
        <city>Turin</city>
        <zip>10124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Headache Unit, University Hospital Vall d'Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Servicio de Neurologia, Hospital Ruber Internacional</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Servicio de Neurologia, Clinica Universidad de Navarra</name>
      <address>
        <city>Pamplona</city>
        <zip>ES-31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Servicio de Neurologia, Hospital Clinico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <zip>ES-46010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hull Royal Infirmary, Neurology Department</name>
      <address>
        <city>Hull</city>
        <state>East Yorkshire</state>
        <zip>HU3 2JZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Birmingham</name>
      <address>
        <city>Birmingham</city>
        <zip>B15 2TT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital Queen</name>
      <address>
        <city>Gateshead</city>
        <zip>NE9 6SX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sunderland Royal Hospital</name>
      <address>
        <city>Sunderland</city>
        <zip>SR4 7TP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Spain</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>December 22, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <last_update_submitted>June 12, 2019</last_update_submitted>
  <last_update_submitted_qc>June 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Migraine Disorders</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/NCT03787238
org study id: GM-18
nct id: NCT03787238
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: Yes
This is a randomized study for the prevention and acute treatment of migraine using open
      label nVNS and standard of care versus standard of care.

      .
A randomized study for the prevention and acute treatment of migraine using open label nVNS
      and standard of care versus standard of care.

      Eligible subjects will participate in a 4 week run-in period after which they will be
      randomized (1:1) to either nVNS and standard of care (nVNS group) or standard of care (SOC
      group) for 12 weeks. The nVNS group will use the nVNS device preventatively and acutely for
      the treatment of migraine. The SOC group will continue to use their regular standard of care
      migraine treatment medications for the duration of the 12 week randomized period.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Reduction in number of migraine days during the last four weeks in the twelve-week randomized period compared with the four-week run-in period
time frame: The last four weeks in the randomization period compared to the four week run-in period.
description: Reduction in number of migraine days during the last four weeks in the twelve-week randomized period compared with the four-week run-in period
measure: Reduction in number of headache days during the last four-weeks in the twelve-week randomized period compared to the four-week run-in period
time frame: The last four weeks in the randomization period compared to the four week run-in period.
description: Reduction in number of headache days during the last four-weeks in the twelve-week randomized period compared to the four-week run-in period
measure: Reduction in number of migraine days and headache days (separately)
time frame: 12 week randomised period
description: Reduction in number of migraine days and headache days (separately) during weeks 1 through 4, 5 through 8 in the 12 week randomised period
measure: Rate of responders for the nVNS group compared to the standard of care group.
time frame: The last four weeks in the randomization period compared to the four week run-in period.
description: Rate of responders (mean reduction in migraine days during the last four weeks in the twelve-week randomization period compared to the four-week run-in period dichotomized as <25% vs. ≥25%, <50% vs ≥50% and <75% vs ≥75%, separately) for the nVNS group compared to the standard of care group.
measure: Acute treatment response for nVNS and standard of care therapies
time frame: 12 week randomised period
description: Acute treatment response for nVNS and standard of care therapies at 30, 60 and 120 minutes post-treatment, for all treated migraine attacks in the twelve-week randomized period
measure: Consistency of response
time frame: 12 week randomised period
description: Consistency of response as defined as the percentage of subjects who achieve treatment response in 25%, 50% and 75% or greater of their attacks, in subjects treating at least two attacks, for nVNS and standard of care therapies for all treated migraine attacks during the randomized period
measure: Safety and tolerability of nVNS as measured by adverse events
time frame: 12 week randomised period
description: Safety and tolerability of nVNS as measured by adverse events
measure: Change in acute headache medication use
time frame: 12 week randomization period compared to the four week run-in period
description: Change in acute headache medication use (proportion of attacks with acute medication use prior to or at 120 minutes post-treatment) for all treated attacks in the twelve-week randomized period compared to the four week run-in period in the nVNS group
measure: Presence or absence of nausea, vomiting, photophobia, phonophobia
time frame: 12 week randomised period
description: Presence or absence of nausea, vomiting, photophobia, phonophobia at 0, 30, 60 and 120 minutes post treatment for nVNS and standard of care therapies for all treated migraine attacks in the randomized period
arm group label: non-invasive Vagus Nerve Stimulation
arm group type: Experimental
description: nVNS (non-invasive vagus nerve stimulation) treatment with the gammaCore Sapphire device and standard of care
arm group label: Standard of Care
arm group type: No Intervention
description: Standard of Care treatment
intervention type: Device
intervention name: non-invasive vagus nerve stimulation
description: non-invasive vagus nerve stimulation using the gammaCore Sapphire device
arm group label: non-invasive Vagus Nerve Stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alexandra Sinclair, MD
role: Principal Investigator
affiliation: University of Birmingham
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
country: Denmark
country: Germany
country: Italy
country: Spain
country: United Kingdom
country: Netherlands
responsible party type: Sponsor
mesh term: Migraine Disorders