<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/NCT01701245</url>
  </required_header>
  <id_info>
    <org_study_id>GC-002</org_study_id>
    <nct_id>NCT01701245</nct_id>
  </id_info>
  <brief_title>Prevention and Acute Treatment of Chronic Cluster Headache Compared to Standard of Care</brief_title>
  <official_title>A Randomized, Multicenter Study for the Prevention and Acute Treatment of Chronic Cluster Headache Using Gammacore, Versus Standard of Care.</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Subjects enrolled into this 10 week study will for the first two weeks document the number of&#xD;
      cluster headaches and the means of treating (medication) of these attacks. Subjects will then&#xD;
      be randomized to into either two groups. The first group is continuing with standard of care&#xD;
      and the second group is treatment with the investigational device (GammaCore) for a period of&#xD;
      4 weeks. After this 4 week period, all subjects will treat with the GammaCore for another 4&#xD;
      week period. It is hypothesized the the treatment group will have a reduction in mean cluster&#xD;
      headaches per week by 50% compared to the standard of care group.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is a prospective randomized controlled multi-center investigation designed for&#xD;
      comparison of two parallel groups, GammaCore® (active treatment) and Standard of Care, SoC,&#xD;
      (control). The study period begins with a 2 week run-in period, followed by a 4 week&#xD;
      comparative period when the subjects are randomized to either active treatment or control&#xD;
      1:1. The comparative period will be followed by a period where all subject will receive&#xD;
      GammaCore® for 4 weeks.After the subject signed the Consent Form for participation the&#xD;
      baseline (visit1) data will be collected. Subject will be informed how to complete the 2 week&#xD;
      diary during the run-in period During the run-in period, all subjects will use stable SoC&#xD;
      according to their individual prescriptions. The subject will record as CH attack regarding&#xD;
      duration and frequency and the use of medication and oxygen.&#xD;
&#xD;
      Once subjects have finalized the run-in period, they are randomized to continue in 4 weeks&#xD;
      comparative period. During this period, the control group continues with stable SoC and the&#xD;
      active group is provided with a GammaCore® device for prophylactic and acute treatment in&#xD;
      addition to the stable SoC Subjects stimulate 3 x 2 times daily as part of the prophylactic&#xD;
      treatment regimen (cervical vagal nerve). Three 90 second stimulations are self-administered&#xD;
      by the subject with 5 minutes between each stimulation on the right side of the neck.&#xD;
&#xD;
      This preventive stimulation regimen is performed:&#xD;
&#xD;
        -  First Daily Treatment - within 1 hour of waking&#xD;
&#xD;
        -  Second Daily Treatment - 7-10 hours following the first daily treatment&#xD;
&#xD;
      Acute CH attack:&#xD;
&#xD;
        -  3 x 90 second treatments consecutively at the onset of pain or symptoms. If the attack&#xD;
           is not aborted within 15 minutes the subject should be informed to take SOC abortive&#xD;
           medication.&#xD;
&#xD;
        -  If an acute cluster headache attack is treated with the GammaCore® device, the subject&#xD;
           will try to work within the preventive treatment window to avoid a preventive treatment&#xD;
           in the 2-hour refractory period following the acute treatment.&#xD;
&#xD;
      A total of minimally 6 stimulations for the preventive part and as needed for the acute&#xD;
      attacks. The active group also continues with the stable SoC during the entire 4 weeks&#xD;
      period. Both groups record all CH attacks in the diary together with medication and oxygen&#xD;
      use. All adverse events shall also be recorded in the diary.&#xD;
&#xD;
      The end of the 4 week comparative period marks the completion of the randomized part of the&#xD;
      study, however all subjects are provided the option to continue to a 4 week GammaCore®&#xD;
      treatment with the same stimulation parameter as during the 4 week randomization period. All&#xD;
      subjects randomized to the SoC group will receive training.&#xD;
&#xD;
      During the entire study period, subjects are allowed to take rescue medication including&#xD;
      oxygen inhalation for abortion of CH attacks. The amount and doses of the medication and&#xD;
      oxygen are recorded in the diary.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">March 2014</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>A Change in the Frequency of Cluster Headache Attacks Per Week</measure>
    <time_frame>4 weeks</time_frame>
    <description>The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain Relief of Headache Attacks</measure>
    <time_frame>baseline (2 weeks) and random period(last 2 weeks)</time_frame>
    <description>The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain&#xD;
mild pain&#xD;
moderate pain&#xD;
severe pain&#xD;
very severe pain</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>10 weeks</time_frame>
    <description>The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)</measure>
    <time_frame>10 weeks (baseline 2 weeks, random 4 weeks and open label 4 weeks)</time_frame>
    <description>The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label.&#xD;
Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index&#xD;
Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">97</enrollment>
  <condition>Chronic Cluster Headache</condition>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention, standard of care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GammaCore</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>GammaCore</intervention_name>
    <description>vagal stimulation</description>
    <arm_group_label>GammaCore</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        1. Signed Informed Consent Form 2. Subjects between the age of 18-70, both genders 3.&#xD;
        Subjects diagnosed with chronic cluster headache for at least 1 year, without remission&#xD;
        periods or with remission periods lasting &lt;1 month, in accordance with the ICHD-II&#xD;
        classification criteria (2ndEd):&#xD;
&#xD;
        a. At least 5 attacks fulfilling the following criteria: i. Severe or very severe&#xD;
        unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes if untreated&#xD;
        ii. Headache is accompanied by at least 1 of the following:&#xD;
&#xD;
          1. Ipsilateral conjunctival injection and/or lacrimation&#xD;
&#xD;
          2. Ipsilateral nasal congestion and/or rhinorrhea&#xD;
&#xD;
          3. Ipsilateral eyelid oedema&#xD;
&#xD;
          4. Ipsilateral forehead and facial sweating&#xD;
&#xD;
          5. Ipsilateral miosis and/or ptosis&#xD;
&#xD;
          6. A sense of restlessness or agitation iii. Attacks have a frequency from 1 every other&#xD;
             day to 8 per day and are not attributed to another disorder iv. Attacks recur over &gt; 1&#xD;
             year without remission periods or with remission periods lasting &lt; 1 month.&#xD;
&#xD;
        4. Has minimum mean attack frequency of 4 CH attacks per week. 5. Is able to distinguish CH&#xD;
        from other headaches (i.e. tension-type headaches).&#xD;
&#xD;
        6. Is capable of completing headache pain self-assessments. 7. Agrees to use the GammaCore®&#xD;
        device as intended and follow all of the requirements of the study, including follow-up&#xD;
        visit requirements.&#xD;
&#xD;
        8. Is willing to keep all concomitant medication stable during the entire study period.&#xD;
&#xD;
        9. Women of child-bearing potential must use 2 methods of contraceptive i.e. hormones and&#xD;
        condom.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Is currently taking CH prophylactic medication for indications other than CH which in&#xD;
             the opinion of the clinician may interfere with the study&#xD;
&#xD;
          2. Has had a change in type or dosage of prophylactic headache medications &lt; 1 month&#xD;
             prior to enrollment&#xD;
&#xD;
          3. Has a history of intracranial or carotid aneurysm, intracranial hemorrhage, brain&#xD;
             tumors or significant head trauma.&#xD;
&#xD;
          4. Has a lesion (including lymphadenopathy), dysaesthesia, previous surgery or abnormal&#xD;
             anatomy at the GammaCore® treatment site.&#xD;
&#xD;
          5. Has other significant pain problem that might confound the study assessments in the&#xD;
             opinion of the investigator.&#xD;
&#xD;
          6. Has known or suspected severe atherosclerotic cardiovascular disease, severe carotid&#xD;
             artery disease (e.g. bruits or history of TIA or CVA), congestive heart failure (CHF),&#xD;
             known severe coronary artery disease or recent myocardial infarction (within 5years).&#xD;
&#xD;
          7. Has had a previous unilateral or bilateral vagotomy.&#xD;
&#xD;
          8. Has uncontrolled high blood pressure.&#xD;
&#xD;
          9. Is currently implanted with an electrical and/or neurostimulator device, including but&#xD;
             not limited to cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain&#xD;
             stimulator, spinal stimulator, bone growth stimulator, or cochlear implant.&#xD;
&#xD;
         10. Has a history of carotid endarterectomy or vascular neck surgery on the right side.&#xD;
&#xD;
         11. Has been implanted with metal cervical spine hardware or has a metallic implant near&#xD;
             the GammaCore® stimulation site.&#xD;
&#xD;
         12. Has a history, the last 12 month, of syncope.&#xD;
&#xD;
         13. Has a history, the last 12 month of seizures.&#xD;
&#xD;
         14. Has a known history or suspicion of substance abuse or addiction, or overuse of acute&#xD;
             headache medication for headaches other than CH.&#xD;
&#xD;
         15. Has psychiatric or cognitive disorder and/or behavioral problems which in the opinion&#xD;
             of the investigator may interfere with the study&#xD;
&#xD;
         16. In the opinion of the investigator the subject is incapable of operating the&#xD;
             GammaCore® device as intended and performing the data collection procedures.&#xD;
&#xD;
         17. Is participating in any other therapeutic clinical investigation or has participated&#xD;
             in a clinical trial in the preceding 30 days.&#xD;
&#xD;
         18. Woman who are pregnant or lactating.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charly Gaul, Dr med</last_name>
    <role>Principal Investigator</role>
    <affiliation>Migräne- und Kopfschmerzklinik Königstein</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Department of Neurology CHR</name>
      <address>
        <city>Liège</city>
        <zip>B-4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Westdeutsches Kopfschmerzzentrum</name>
      <address>
        <city>Hufelandstr. 26</city>
        <state>Essen</state>
        <zip>D-45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurologische Klinik und Poliklinik</name>
      <address>
        <city>Berlin</city>
        <zip>D-10117</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Krankenhaus Lindenbrunn, Department of Neurology</name>
      <address>
        <city>Coppenbrügge</city>
        <zip>D-31863</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>Department of Neurology, University of Munich</name>
      <address>
        <city>Munich</city>
        <zip>D-813 77</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Regional Referral Headache Centre Sant' Andrea Hospital</name>
      <address>
        <city>Rome</city>
        <zip>IT-00189</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Southern Hospital, Neurology Department</name>
      <address>
        <city>Glasgow</city>
        <state>Scotland</state>
        <zip>G51 4TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hull Royal Infirmary, Neurology Department</name>
      <address>
        <city>Hull</city>
        <zip>HU3 2JZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Walton Centre, Neurology Department</name>
      <address>
        <city>Liverpool</city>
        <zip>L9 7LJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>March 2016</verification_date>
  <study_first_submitted>October 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <results_first_submitted>September 30, 2015</results_first_submitted>
  <results_first_submitted_qc>March 23, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">April 25, 2016</results_first_posted>
  <last_update_submitted>March 23, 2016</last_update_submitted>
  <last_update_submitted_qc>March 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 25, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vagus nerve stimulation</keyword>
  <keyword>vagal nerve stimulation</keyword>
  <keyword>nVNS</keyword>
  <keyword>VNS</keyword>
  <keyword>cluster headache</keyword>
  <keyword>chronic</keyword>
  <keyword>non invasive</keyword>
  <keyword>gammacore</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cluster Headache</mesh_term>
    <mesh_term>Headache</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Not planned to share individual data</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Standard of Care</title>
          <description>No intervention, standard of care</description>
        </group>
        <group group_id="P2">
          <title>GammaCore</title>
          <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>FAS Unmatched Data</title>
              <participants_list>
                <participants group_id="P1" count="48">1 patient protocol violation</participants>
                <participants group_id="P2" count="45">3 patients protocol violation</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>FAS Matched Data</title>
              <participants_list>
                <participants group_id="P1" count="42"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
                <participants group_id="P2" count="33"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Did not complete the open label period</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Standard of Care</title>
          <description>No intervention, standard of care</description>
        </group>
        <group group_id="B2">
          <title>GammaCore</title>
          <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="49"/>
            <count group_id="B2" value="48"/>
            <count group_id="B3" value="97"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="42.3" spread="11.0"/>
                    <measurement group_id="B2" value="45.4" spread="11.0"/>
                    <measurement group_id="B3" value="43.8" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Belgium</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>A Change in the Frequency of Cluster Headache Attacks Per Week</title>
        <description>The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.</description>
        <time_frame>4 weeks</time_frame>
        <population>Full analysis set (FAS), matched group.</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care</title>
            <description>No intervention, standard of care</description>
          </group>
          <group group_id="O2">
            <title>GammaCore</title>
            <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>A Change in the Frequency of Cluster Headache Attacks Per Week</title>
          <description>The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.</description>
          <population>Full analysis set (FAS), matched group.</population>
          <units>CH attacks per week</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.0" spread="7.6"/>
                    <measurement group_id="O2" value="-7.6" spread="6.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pain Relief of Headache Attacks</title>
        <description>The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain&#xD;
mild pain&#xD;
moderate pain&#xD;
severe pain&#xD;
very severe pain</description>
        <time_frame>baseline (2 weeks) and random period(last 2 weeks)</time_frame>
        <population>Median severity per subject in run in period (14 days) and the last 14 Days in the treatment period.&#xD;
FAS matched data set</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care</title>
            <description>No intervention, standard of care</description>
          </group>
          <group group_id="O2">
            <title>GammaCore</title>
            <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>Pain Relief of Headache Attacks</title>
          <description>The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain&#xD;
mild pain&#xD;
moderate pain&#xD;
severe pain&#xD;
very severe pain</description>
          <population>Median severity per subject in run in period (14 days) and the last 14 Days in the treatment period.&#xD;
FAS matched data set</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mild random</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate random</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe random</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Very severe baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Very severe random</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events</title>
        <description>The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.</description>
        <time_frame>10 weeks</time_frame>
        <population>Safety population The Adverse Device effects are reported as Adverse Event, the device effects are AEs that are considered related to the treatment. Graded mild, moderate and severe</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care</title>
            <description>No intervention, standard of care</description>
          </group>
          <group group_id="O2">
            <title>GammaCore</title>
            <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.</description>
          <population>Safety population The Adverse Device effects are reported as Adverse Event, the device effects are AEs that are considered related to the treatment. Graded mild, moderate and severe</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)</title>
        <description>The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label.&#xD;
Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index&#xD;
Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state</description>
        <time_frame>10 weeks (baseline 2 weeks, random 4 weeks and open label 4 weeks)</time_frame>
        <population>Changes between baseline and randomized period.Randomized period and open label. FAS Unmatched data.</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care</title>
            <description>No intervention, standard of care</description>
          </group>
          <group group_id="O2">
            <title>GammaCore</title>
            <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
          </group>
        </group_list>
        <measure>
          <title>EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)</title>
          <description>The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label.&#xD;
Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index&#xD;
Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state</description>
          <population>Changes between baseline and randomized period.Randomized period and open label. FAS Unmatched data.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline vs. Randomized period</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.049" lower_limit="-0.837" upper_limit="0.856"/>
                    <measurement group_id="O2" value="0.145" lower_limit="-0.532" upper_limit="0.807"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Randomized period vs. Open label perios</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.078" lower_limit="-0.601" upper_limit="1.01"/>
                    <measurement group_id="O2" value="0.155" lower_limit="-0.568" upper_limit="1.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VAS Baseline vs. Randomized period</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.27" lower_limit="-81.0" upper_limit="40.0"/>
                    <measurement group_id="O2" value="9.20" lower_limit="-20.0" upper_limit="40.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VAS Randomized period vs. Open label</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.36" lower_limit="-50.0" upper_limit="48.0"/>
                    <measurement group_id="O2" value="10.79" lower_limit="-26.0" upper_limit="55.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>18 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Standard of Care</title>
          <description>No intervention, standard of care</description>
        </group>
        <group group_id="E2">
          <title>GammaCore</title>
          <description>Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.&#xD;
GammaCore: vagal stimulation</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>Cholecystitis</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <description>Hospitalization/Not related</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title vocab="Herpes simplex infec">Genital herpes simplex</sub_title>
                <description>Hospitalization/Not related</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title vocab="Scrotum Haematoma">Scrotal Haematoma</sub_title>
                <description>Hospitalization/Not related</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title vocab="Cluster headache">Cluster headache</sub_title>
                <description>Hospitalization/Not related</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 17.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="49"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Annelie Andersson</name_or_title>
      <organization>electroCore LLC</organization>
      <phone>+46 721 803076</phone>
      <email>annelie.andersson@electrocorellc.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01701245
org study id: GC-002
nct id: NCT01701245
lead sponsor: 
has dmc: No
Subjects enrolled into this 10 week study will for the first two weeks document the number of
      cluster headaches and the means of treating (medication) of these attacks. Subjects will then
      be randomized to into either two groups. The first group is continuing with standard of care
      and the second group is treatment with the investigational device (GammaCore) for a period of
      4 weeks. After this 4 week period, all subjects will treat with the GammaCore for another 4
      week period. It is hypothesized the the treatment group will have a reduction in mean cluster
      headaches per week by 50% compared to the standard of care group.
The study is a prospective randomized controlled multi-center investigation designed for
      comparison of two parallel groups, GammaCore® (active treatment) and Standard of Care, SoC,
      (control). The study period begins with a 2 week run-in period, followed by a 4 week
      comparative period when the subjects are randomized to either active treatment or control
      1:1. The comparative period will be followed by a period where all subject will receive
      GammaCore® for 4 weeks.After the subject signed the Consent Form for participation the
      baseline (visit1) data will be collected. Subject will be informed how to complete the 2 week
      diary during the run-in period During the run-in period, all subjects will use stable SoC
      according to their individual prescriptions. The subject will record as CH attack regarding
      duration and frequency and the use of medication and oxygen.

      Once subjects have finalized the run-in period, they are randomized to continue in 4 weeks
      comparative period. During this period, the control group continues with stable SoC and the
      active group is provided with a GammaCore® device for prophylactic and acute treatment in
      addition to the stable SoC Subjects stimulate 3 x 2 times daily as part of the prophylactic
      treatment regimen (cervical vagal nerve). Three 90 second stimulations are self-administered
      by the subject with 5 minutes between each stimulation on the right side of the neck.

      This preventive stimulation regimen is performed:

        -  First Daily Treatment - within 1 hour of waking

        -  Second Daily Treatment - 7-10 hours following the first daily treatment

      Acute CH attack:

        -  3 x 90 second treatments consecutively at the onset of pain or symptoms. If the attack
           is not aborted within 15 minutes the subject should be informed to take SOC abortive
           medication.

        -  If an acute cluster headache attack is treated with the GammaCore® device, the subject
           will try to work within the preventive treatment window to avoid a preventive treatment
           in the 2-hour refractory period following the acute treatment.

      A total of minimally 6 stimulations for the preventive part and as needed for the acute
      attacks. The active group also continues with the stable SoC during the entire 4 weeks
      period. Both groups record all CH attacks in the diary together with medication and oxygen
      use. All adverse events shall also be recorded in the diary.

      The end of the 4 week comparative period marks the completion of the randomized part of the
      study, however all subjects are provided the option to continue to a 4 week GammaCore®
      treatment with the same stimulation parameter as during the 4 week randomization period. All
      subjects randomized to the SoC group will receive training.

      During the entire study period, subjects are allowed to take rescue medication including
      oxygen inhalation for abortion of CH attacks. The amount and doses of the medication and
      oxygen are recorded in the diary.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: A Change in the Frequency of Cluster Headache Attacks Per Week
time frame: 4 weeks
description: The primary endpoint is the reduction in mean number of CH attacks per week. The number of CH attacks will be calculated as the sum of all attacks over the days in the run-in period and divided by the number of weeks, respectively for the last 14 days of treatment during the randomised phase. The reduction will then be the number of CH attacks during treatment period (last 14 days of the randomized treatment period) - number of CH attacks during run-in.
measure: Pain Relief of Headache Attacks
time frame: baseline (2 weeks) and random period(last 2 weeks)
description: The median pain during baseline (2 weeks) will be compared with the last 14 days of the treatment period Scale 0-4 0= no pain
mild pain
moderate pain
severe pain
very severe pain
measure: Adverse Events
time frame: 10 weeks
description: The frequency of device effects will be compared between the two treatment groups. Only effects which are new after baseline or have increased severity after baseline will be used in the comparison.
measure: EQ-5D-3L (EuroQoL 5 Questions and 3 Answering Levels) and a VAS (Visual Analogue Scale)
time frame: 10 weeks (baseline 2 weeks, random 4 weeks and open label 4 weeks)
description: The EQ-5D-3L (EuroQoL 5 questions and 3 answering levels) during the run-in period will be compared with the EQ-5D-3L during the treatment period. And treatment period will be compared to open label.
Rating of questions Level 1 no problems Level 2 some problems Level 3 Significant problems Worst case is 15 points and best case is 5 points using index
Visual analogue scale VAS 0-100 where 0 is the worst imaginable health state and 100 the best imaginable health state
arm group label: Standard of care
arm group type: No Intervention
description: No intervention, standard of care
arm group label: GammaCore
arm group type: Active Comparator
description: Three stimulation treatments 2x/day 7 to 10 hours apart from one another. In addition, three stimulation treatments at the time of onset of symptoms of a headache attack.
intervention type: Device
intervention name: GammaCore
description: vagal stimulation
arm group label: GammaCore
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Charly Gaul, Dr med
role: Principal Investigator
affiliation: Migräne- und Kopfschmerzklinik Königstein
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: Germany
country: Italy
country: United Kingdom
responsible party type: Sponsor
mesh term: Cluster Headache
mesh term: Headache
sharing ipd: No
ipd description: Not planned to share individual data
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 