<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/NCT03026101</url>
  </required_header>
  <id_info>
    <org_study_id>2017-8335</org_study_id>
    <nct_id>NCT03026101</nct_id>
  </id_info>
  <brief_title>Understanding the Pathophysiology of Migraine Pain</brief_title>
  <official_title>Understanding the Role of the External Carotid Artery in the Pathophysiology of Migraine Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Montefiore Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Montefiore Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Migraine is the most common headache disorder, prevalent in 18% of females and 6% of males.&#xD;
      Emergency room visits, physician consults, hospitalizations, medications, and indirect costs&#xD;
      such as lost work days and decreased productivity place the global economic burden of&#xD;
      migraines at over 20 billion dollars. It is prevalent in 28 million people in the US alone.&#xD;
      Symptoms include unilateral, throbbing, debilitating headache pain accompanied by nausea,&#xD;
      vomiting, photophobia, and phonophobia. Upwards of 75% of migraine patients have reduced&#xD;
      functionability, have lost time at work, and 1/3 of patients require bed rest to manage the&#xD;
      symptoms. The health-related impact on quality of life was comparable with that experienced&#xD;
      by patients with congestive heart failure, hypertension, or diabetes.&#xD;
&#xD;
      While the burden of migraines on our society is clear, the pathophysiology of migraines&#xD;
      remains largely unknown. The trigeminovascular system, including the external and internal&#xD;
      carotid arteries and their associated sensory fibers which subserve the head have long been&#xD;
      implicated in the pain and cutaneous allodynia experienced by migraine patients. Wolff in&#xD;
      1953, was the first to posit that migraine headache pain is the caused by dilation or&#xD;
      circumferential expansion of the extracranial carotid artery. He demonstrated that&#xD;
      migraineurs had twice the pulse amplitude in their external carotid arteries compared to&#xD;
      control subjects and these changes were directly correlated to migraine symptoms. In a 2008&#xD;
      study, randomized migraineurs received nitroglycerin via peripheral IV or placebo for 20&#xD;
      minutes prior to obtaining magnetic resonance angiography (MRA). Nitroglycerin, a potent&#xD;
      dilator of blood vessels, reliably induced migraine-like pain in up to 80% of patients, and&#xD;
      transient dilation of vessels of up to nearly 40%, mostly in the extracranial vessels.&#xD;
      Sumatriptan's efficacy in migraine relief provides further evidence for this theory, as it is&#xD;
      a selective extracranial vessel constrictor which does not cross the blood brain barrier.&#xD;
&#xD;
      The goal of this current work is to utilize the direct, real-time angiography, which provides&#xD;
      a high resolution map of vasculature, and demonstrate changes in vessel flow in patients who&#xD;
      have migraine headache attacks. This information may guide therapeutic interventions in the&#xD;
      future in order to better treat these migraine patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goals of the current study will be to demonstrate time-linked headache pain after&#xD;
      super-selectively administration of vasodilatory medications to external carotid artery&#xD;
      branches, and then observe vessel changes and presumed headache relief with transient&#xD;
      occlusion of the same vessel. This work will be the first study to attempt to correlate the&#xD;
      onset of headache pain with selective vessel dilation as seen on angiography, which has&#xD;
      spatial and temporal resolution far superior to MRA imaging. It will also test the effect of&#xD;
      transient vessel occlusion in this setting for possible relief of symptoms. This novel&#xD;
      approach to migraine evaluation could advance the understanding of the disorder and steer&#xD;
      future research towards more effective management of migraine pain. Only patients who have&#xD;
      failed all medical and non-invasive therapies will be considered for this study.&#xD;
&#xD;
      Subjects will be evaluated by history and physical during a clinic visit for their migraines&#xD;
      and the 'pre-angiography' screening will be performed at that time. A thorough history of&#xD;
      their migraine symptomatology, if they agree to participate, will be obtained via&#xD;
      questionnaire, including: severity, location, quality, alleviating and exacerbating symptoms,&#xD;
      medications used, associated symptoms, frequency, and degree of debilitation. This&#xD;
      information will be collected regarding their migraines uniquely for this study. The patients&#xD;
      will also be given a headache log with each one of these measures as a column with space in&#xD;
      each row to describe individual migraine episodes between their first clinic visit and their&#xD;
      angiogram date. After this clinic visit, they will be scheduled for angiography between 2 and&#xD;
      4 weeks for the evaluation of their migraines. Their headache logs will be collected prior to&#xD;
      their procedures.&#xD;
&#xD;
      The main portion of this study will occur during a single angiography session and the&#xD;
      following 5 hours post-procedure period during which the patient will be monitored closely as&#xD;
      part of standard post-angiogram care. An anesthesiologist will be present throughout the&#xD;
      procedure and available for medication review and administration as needed. The patients will&#xD;
      sign a consent form at the start of the day and will be reminded that they have the option of&#xD;
      not participating in the study and continuing their normal migraine treatment. If they do&#xD;
      choose to participate, the patients will be brought to the angiography suite and transferred&#xD;
      to the angiogram table. The patient will be prepped and draped in standard fashion for an&#xD;
      angiogram and given instructions regarding the procedure for the day. The patient will&#xD;
      receive local lidocaine at their groin site to minimize discomfort during standard arterial&#xD;
      access for the purposes of the angiogram. Catheterization will commence into the external&#xD;
      carotid artery. At this time, the patient's headache history will guide the decision for&#xD;
      first vessel cannulation. If the patient has frontal migraines, the internal maxillary artery&#xD;
      will be cannulated, for parietal headaches the focus will be on the superficial temporal&#xD;
      artery, and the occipital artery for posterior, occipitally located symptoms, all on the side&#xD;
      of the patient's migraines. A microcatheter will be placed at the origin of each respective&#xD;
      artery and a control contrast injection will be performed to determine baseline vessel&#xD;
      caliber and blood flow. Patients will be asked at this time if they are experiencing any pain&#xD;
      or discomfort. If none, nitroglycerin will be drawn up and injected at a volume of 200µg&#xD;
      diluted in 10ml saline into these vessels only. This is a standard injection dose for&#xD;
      vasodilation for this medication and it is routinely available and used to treat vasospasm,&#xD;
      or vasoconstriction that occurs after subarachnoid hemorrhage in the angiography suite. This&#xD;
      dose has also been used in several cranial and cardiac studies and has not been association&#xD;
      with adverse reactions related to systemic spread. The expectation is that this small dose&#xD;
      will not reach systemic circulation. After 5 minutes, another contrast run will be performed&#xD;
      to determine any change in vessel size and the patient will be questioned about any headache&#xD;
      symptoms. After another 5 minutes, another contrast run will be performed to see if the&#xD;
      nitroglycerin is still effective. If the patient describes no symptoms, the focus will be&#xD;
      shifted to one of the other 2 external carotid artery branches to test them for the induction&#xD;
      of headaches using the same nitroglycerin protocol. Each vessel will be evaluated for a full&#xD;
      10 minutes and if no vessel causes headache pain, the study will be terminated after a final&#xD;
      control injection and femoral sheath removal. Pressure on the groin will be held for 20&#xD;
      minutes and the patient will be taken to the recovery room and monitored lying flat, as in&#xD;
      standard fashion for 5 hours before being discharged home in order to prevent groin hematoma.&#xD;
      They will again be evaluated for headaches or pain hourly until discharge, and be given&#xD;
      another headache log to complete prior to their 2 week follow-up visit. The headache log will&#xD;
      be collected at that time and this will complete the study for the patient.&#xD;
&#xD;
      If any vessel immediately, or with time produces headache pain, the patient will be queried&#xD;
      regarding the type and quality of the headache, and asked if it is similar to their&#xD;
      migraines. A 10 minute angiogram will be repeated at the vessel evaluated. With persistent&#xD;
      headaches, a microballoon will be brought to the vessel origin, and it will be inflated to&#xD;
      block flow in this vessel for 5 minutes before being deflated. As stated previously, there is&#xD;
      no risk to occlusion of these vessels permanently, and certainly not temporarily as will be&#xD;
      performed as part of this protocol. These non-critical vessels have dense anastomotic&#xD;
      networks and are safe to occlude. Symptoms will be evaluated to see if any subside as a&#xD;
      result of their occlusion. Five minutes after the balloon is deflated, another contrast run&#xD;
      will be performed to evaluate the caliber of the studied vessel. After this run, the groin&#xD;
      sheath will be removed and the above protocol will be followed until outpatient follow-up. If&#xD;
      headache symptoms do not subside, the patient will be administered standard pain medication,&#xD;
      fentanyl, which is given routinely during angiography at a dose of 25mcg to abate their pain.&#xD;
      This is a low, tolerable, and safe dose that will be given with the assistance of our&#xD;
      anesthesia colleagues, if necessary. Their headache pain will be closely monitored during the&#xD;
      5 hour recovery period, and given 1 more 25mcg dose during this period in order to fully&#xD;
      subside any pain the patient still may have.&#xD;
&#xD;
      This angiogram will take approximately 30 minutes to complete, and it is a low risk&#xD;
      procedure.. The vessels studied diagnostically will be solely extracranial and completely&#xD;
      separate from intracranial vessels. Any anomalous communication identified between&#xD;
      extracranial and intracranial vessels will automatically disqualify a patient from&#xD;
      participation in this study.&#xD;
&#xD;
      Despite some minor discomfort from the groin puncture for the patient, with the assistance of&#xD;
      an anesthesiologist the pain intra- and post-procedurally experienced by patients will be&#xD;
      well controlled. The patient may also opt to receive the rescue pain medication at any time&#xD;
      during the angiogram and discontinue the study.&#xD;
&#xD;
      As stated previously, the extracranial vascular circulation has a large anastomotic network&#xD;
      such that a single vessel sacrifice can be performed without great risk. These vessels are&#xD;
      sacrificed without sequelae intraoperatively routinely when performing craniotomies. In cases&#xD;
      where a provocative artery can be found, occlusion of that vessel can lead to improved&#xD;
      symptoms, as tested by temporary balloon occlusion without great risk. It is the hope that&#xD;
      this pilot work to guide future interventions to control blood flow in these offending&#xD;
      vessels, to see if migraines abate permanently with vessel removal from circulation. If these&#xD;
      hypotheses are correct, interventions may be created to minimize patient's need for&#xD;
      medication, improve their quality of life, and free them from the debilitation of their&#xD;
      migraines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Migraine</measure>
    <time_frame>10 minutes</time_frame>
    <description>The reporting of migraine-like pain after nitroglycerin administration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: severity measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Severity of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: frequency measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Frequency of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: quality measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Quality of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: location measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Location of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: alleviating factor measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Alleviating factors of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: aggravating factor measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Aggravating factors of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: associated symptom measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Associated symptoms of migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log pre-procedure: therapies utilized measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Therapies utilized for migraines for 2 weeks prior to angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Artery dilation</measure>
    <time_frame>10 minutes</time_frame>
    <description>Enlargement of the diameter of the vessel of interest after nitroglycerin administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine pain relief</measure>
    <time_frame>20 minutes</time_frame>
    <description>Relief of induced migraine pain with temporary balloon occlusion of the dilated artery. Standard pain medication will also be available for treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse reactions</measure>
    <time_frame>6 hours</time_frame>
    <description>Monitoring for retroperitoneal hematoma, vascular injury, infection, contrast reaction, worsening contralateral headache symptoms, new neurologic deficit peri-procedurally until discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: severity measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Severity of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: frequency measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Frequency of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: quality measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Quality of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: location measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Location of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: alleviating factors measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Alleviating factors of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: aggravating factor measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Aggravating factors of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: associated factor measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Associated symptoms of migraines for 2 weeks post-angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Migraine log follow-up post-procedure: therapies utilized measure</measure>
    <time_frame>2 weeks</time_frame>
    <description>Therapies utilized for 2 weeks after angiogram until follow-up clinic visit</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Migraine Disorders</condition>
  <condition>Migraine, Classic</condition>
  <condition>Migraine Without Aura</condition>
  <arm_group>
    <arm_group_label>Migraine Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects who will be administered 200 micrograms of nitroglycerin once into branches of their external carotid artery to determine the role of dilation of this artery to cause migraine-like pain</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Nitroglycerin</intervention_name>
    <description>Intra-arterial adminstration to dilate external carotid artery branches to replicate migraine pain</description>
    <arm_group_label>Migraine Intervention</arm_group_label>
    <other_name>Nitrostat</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects with a documented diagnosis of migraine by a neurologist&#xD;
&#xD;
          -  Subjects refractory to standard migraine therapy with persistent severe, debilitating&#xD;
             symptoms&#xD;
&#xD;
          -  Subjects without changes to their neurological exam within the preceding 6 months&#xD;
&#xD;
          -  Migraines at least twice a month&#xD;
&#xD;
          -  Migraines unique and distinguishable from other non-migraine headache pain&#xD;
&#xD;
          -  Subjects must sign a consent form for both angiography and for participation in this&#xD;
             study, and must be willing to undergo angiography for the evaluation of their symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects taking vasoactive drugs including epinephrine, norepinephrine, dopamine,&#xD;
             dobutamine, isoprenaline, dopexamine, milrinone, amrinon, levosimendan, glucagon,&#xD;
             phenylephrine, metaraminol, ephedrine, vasopressin, digoxin, and levothyroxine&#xD;
&#xD;
          -  Subjects with underlying cardiac pathology including but not limited to coronary&#xD;
             artery disease, heart attacks, or severe atherosclerosis,&#xD;
&#xD;
          -  Subjects with severe pulmonary disease requiring supplemental oxygen therapy&#xD;
&#xD;
          -  Subjects taking medications similar to nitroglycerin such as phosphodiesterase&#xD;
             inhibitors&#xD;
&#xD;
          -  Subjects with contraindications to nitroglycerin or calcium channel blocker use&#xD;
&#xD;
          -  Subjects who have had coffee, tea, or alcohol in the 12 hours before the start of the&#xD;
             angiogram&#xD;
&#xD;
          -  Subjects having other headache conditions or pain syndromes&#xD;
&#xD;
          -  Subjects with prior intracranial therapies or craniotomies for management of any&#xD;
             intracranial lesions&#xD;
&#xD;
          -  Subjects in whom the angiography demonstrates severe vessel tortuosity or stenosis,&#xD;
             vasospasm not responsive to medical therapy, or abnormal communication between&#xD;
             intracranial and extracranial vessels either in the past or during the study procedure&#xD;
&#xD;
          -  Subjects who are not able to reliably report symptoms&#xD;
&#xD;
          -  Subjects who do not consent to participate&#xD;
&#xD;
          -  Subjects who are pregnant and children&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David J Altschul, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Montefiore Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10467</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Evans MS, Cheng X, Jeffry JA, Disney KE, Premkumar LS. Sumatriptan inhibits TRPV1 channels in trigeminal neurons. Headache. 2012 May;52(5):773-84. doi: 10.1111/j.1526-4610.2011.02053.x. Epub 2012 Jan 30.</citation>
    <PMID>22289052</PMID>
  </reference>
  <reference>
    <citation>Totaro R, De Matteis G, Marini C, Baldassarre M, Carolei A. Sumatriptan and cerebral blood flow velocity changes during migraine attacks. Headache. 1997 Nov-Dec;37(10):635-9. doi: 10.1046/j.1526-4610.1997.3710635.x.</citation>
    <PMID>9439084</PMID>
  </reference>
  <reference>
    <citation>Shevel E. The trigeminovascular system--quo vadis? Headache. 2009 May;49(5):785-6. doi: 10.1111/j.1526-4610.2009.01415.x. No abstract available.</citation>
    <PMID>19456890</PMID>
  </reference>
  <reference>
    <citation>Shevel E. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm (Vienna). 2011 Apr;118(4):525-30. doi: 10.1007/s00702-010-0517-1. Epub 2011 Jan 5.</citation>
    <PMID>21207080</PMID>
  </reference>
  <reference>
    <citation>Shevel E. The extracranial vascular theory of migraine--a great story confirmed by the facts. Headache. 2011 Mar;51(3):409-417. doi: 10.1111/j.1526-4610.2011.01844.x.</citation>
    <PMID>21352215</PMID>
  </reference>
  <reference>
    <citation>Beekman R, Nijssen PC, van Rooij WJ, Wijnalda D. Migraine with aura after intracranial endovascular procedures. Headache. 2001 Apr;41(4):410-3. doi: 10.1046/j.1526-4610.2001.111006410.x.</citation>
    <PMID>11318889</PMID>
  </reference>
  <reference>
    <citation>Choi KS, Lee JH, Yi HJ, Chun HJ, Lee YJ, Kim DW. Incidence and risk factors of postoperative headache after endovascular coil embolization of unruptured intracranial aneurysms. Acta Neurochir (Wien). 2014 Jul;156(7):1281-7. doi: 10.1007/s00701-014-2095-8. Epub 2014 May 7. Erratum In: Acta Neurochir (Wien). 2014 Sep;156(9):1829.</citation>
    <PMID>24801821</PMID>
  </reference>
  <reference>
    <citation>Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014 Mar;137(Pt 3):779-94. doi: 10.1093/brain/awt369. Epub 2014 Feb 5.</citation>
    <PMID>24501094</PMID>
  </reference>
  <reference>
    <citation>Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet. 2010 Aug 21;376(9741):645-55. doi: 10.1016/S0140-6736(10)60323-6. Epub 2010 Apr 21.</citation>
    <PMID>20416945</PMID>
  </reference>
  <reference>
    <citation>Meents JE, Hoffmann J, Chaplan SR, Neeb L, Schuh-Hofer S, Wickenden A, Reuter U. Two TRPV1 receptor antagonists are effective in two different experimental models of migraine. J Headache Pain. 2015;16:57. doi: 10.1186/s10194-015-0539-z. Epub 2015 Jun 24.</citation>
    <PMID>26109436</PMID>
  </reference>
  <reference>
    <citation>Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009 Jan-Feb;12(1):55-64. doi: 10.1111/j.1524-4733.2008.00404.x. Epub 2008 Jul 30.</citation>
    <PMID>18671771</PMID>
  </reference>
  <reference>
    <citation>Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain: a systematic review and meta-analysis. Neurology. 2013 Oct 1;81(14):1260-8. doi: 10.1212/WNL.0b013e3182a6cb32. Epub 2013 Aug 28.</citation>
    <PMID>23986301</PMID>
  </reference>
  <reference>
    <citation>Starling AJ, Dodick DW. Best practices for patients with chronic migraine: burden, diagnosis, and management in primary care. Mayo Clin Proc. 2015 Mar;90(3):408-14. doi: 10.1016/j.mayocp.2015.01.010.</citation>
    <PMID>25744118</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 27, 2016</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>February 5, 2023</last_update_submitted>
  <last_update_submitted_qc>February 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Montefiore Medical Center</investigator_affiliation>
    <investigator_full_name>David Altschul</investigator_full_name>
    <investigator_title>Chief, The Leo M. Davidoff Department of Neurological Surgery Division of Cerebrovascular Neurosurgery</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Migraine Disorders</mesh_term>
    <mesh_term>Migraine without Aura</mesh_term>
    <mesh_term>Migraine with Aura</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitroglycerin</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/NCT03026101
org study id: 2017-8335
nct id: NCT03026101
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Migraine is the most common headache disorder, prevalent in 18% of females and 6% of males.
      Emergency room visits, physician consults, hospitalizations, medications, and indirect costs
      such as lost work days and decreased productivity place the global economic burden of
      migraines at over 20 billion dollars. It is prevalent in 28 million people in the US alone.
      Symptoms include unilateral, throbbing, debilitating headache pain accompanied by nausea,
      vomiting, photophobia, and phonophobia. Upwards of 75% of migraine patients have reduced
      functionability, have lost time at work, and 1/3 of patients require bed rest to manage the
      symptoms. The health-related impact on quality of life was comparable with that experienced
      by patients with congestive heart failure, hypertension, or diabetes.

      While the burden of migraines on our society is clear, the pathophysiology of migraines
      remains largely unknown. The trigeminovascular system, including the external and internal
      carotid arteries and their associated sensory fibers which subserve the head have long been
      implicated in the pain and cutaneous allodynia experienced by migraine patients. Wolff in
      1953, was the first to posit that migraine headache pain is the caused by dilation or
      circumferential expansion of the extracranial carotid artery. He demonstrated that
      migraineurs had twice the pulse amplitude in their external carotid arteries compared to
      control subjects and these changes were directly correlated to migraine symptoms. In a 2008
      study, randomized migraineurs received nitroglycerin via peripheral IV or placebo for 20
      minutes prior to obtaining magnetic resonance angiography (MRA). Nitroglycerin, a potent
      dilator of blood vessels, reliably induced migraine-like pain in up to 80% of patients, and
      transient dilation of vessels of up to nearly 40%, mostly in the extracranial vessels.
      Sumatriptan's efficacy in migraine relief provides further evidence for this theory, as it is
      a selective extracranial vessel constrictor which does not cross the blood brain barrier.

      The goal of this current work is to utilize the direct, real-time angiography, which provides
      a high resolution map of vasculature, and demonstrate changes in vessel flow in patients who
      have migraine headache attacks. This information may guide therapeutic interventions in the
      future in order to better treat these migraine patients.
The goals of the current study will be to demonstrate time-linked headache pain after
      super-selectively administration of vasodilatory medications to external carotid artery
      branches, and then observe vessel changes and presumed headache relief with transient
      occlusion of the same vessel. This work will be the first study to attempt to correlate the
      onset of headache pain with selective vessel dilation as seen on angiography, which has
      spatial and temporal resolution far superior to MRA imaging. It will also test the effect of
      transient vessel occlusion in this setting for possible relief of symptoms. This novel
      approach to migraine evaluation could advance the understanding of the disorder and steer
      future research towards more effective management of migraine pain. Only patients who have
      failed all medical and non-invasive therapies will be considered for this study.

      Subjects will be evaluated by history and physical during a clinic visit for their migraines
      and the 'pre-angiography' screening will be performed at that time. A thorough history of
      their migraine symptomatology, if they agree to participate, will be obtained via
      questionnaire, including: severity, location, quality, alleviating and exacerbating symptoms,
      medications used, associated symptoms, frequency, and degree of debilitation. This
      information will be collected regarding their migraines uniquely for this study. The patients
      will also be given a headache log with each one of these measures as a column with space in
      each row to describe individual migraine episodes between their first clinic visit and their
      angiogram date. After this clinic visit, they will be scheduled for angiography between 2 and
      4 weeks for the evaluation of their migraines. Their headache logs will be collected prior to
      their procedures.

      The main portion of this study will occur during a single angiography session and the
      following 5 hours post-procedure period during which the patient will be monitored closely as
      part of standard post-angiogram care. An anesthesiologist will be present throughout the
      procedure and available for medication review and administration as needed. The patients will
      sign a consent form at the start of the day and will be reminded that they have the option of
      not participating in the study and continuing their normal migraine treatment. If they do
      choose to participate, the patients will be brought to the angiography suite and transferred
      to the angiogram table. The patient will be prepped and draped in standard fashion for an
      angiogram and given instructions regarding the procedure for the day. The patient will
      receive local lidocaine at their groin site to minimize discomfort during standard arterial
      access for the purposes of the angiogram. Catheterization will commence into the external
      carotid artery. At this time, the patient's headache history will guide the decision for
      first vessel cannulation. If the patient has frontal migraines, the internal maxillary artery
      will be cannulated, for parietal headaches the focus will be on the superficial temporal
      artery, and the occipital artery for posterior, occipitally located symptoms, all on the side
      of the patient's migraines. A microcatheter will be placed at the origin of each respective
      artery and a control contrast injection will be performed to determine baseline vessel
      caliber and blood flow. Patients will be asked at this time if they are experiencing any pain
      or discomfort. If none, nitroglycerin will be drawn up and injected at a volume of 200µg
      diluted in 10ml saline into these vessels only. This is a standard injection dose for
      vasodilation for this medication and it is routinely available and used to treat vasospasm,
      or vasoconstriction that occurs after subarachnoid hemorrhage in the angiography suite. This
      dose has also been used in several cranial and cardiac studies and has not been association
      with adverse reactions related to systemic spread. The expectation is that this small dose
      will not reach systemic circulation. After 5 minutes, another contrast run will be performed
      to determine any change in vessel size and the patient will be questioned about any headache
      symptoms. After another 5 minutes, another contrast run will be performed to see if the
      nitroglycerin is still effective. If the patient describes no symptoms, the focus will be
      shifted to one of the other 2 external carotid artery branches to test them for the induction
      of headaches using the same nitroglycerin protocol. Each vessel will be evaluated for a full
      10 minutes and if no vessel causes headache pain, the study will be terminated after a final
      control injection and femoral sheath removal. Pressure on the groin will be held for 20
      minutes and the patient will be taken to the recovery room and monitored lying flat, as in
      standard fashion for 5 hours before being discharged home in order to prevent groin hematoma.
      They will again be evaluated for headaches or pain hourly until discharge, and be given
      another headache log to complete prior to their 2 week follow-up visit. The headache log will
      be collected at that time and this will complete the study for the patient.

      If any vessel immediately, or with time produces headache pain, the patient will be queried
      regarding the type and quality of the headache, and asked if it is similar to their
      migraines. A 10 minute angiogram will be repeated at the vessel evaluated. With persistent
      headaches, a microballoon will be brought to the vessel origin, and it will be inflated to
      block flow in this vessel for 5 minutes before being deflated. As stated previously, there is
      no risk to occlusion of these vessels permanently, and certainly not temporarily as will be
      performed as part of this protocol. These non-critical vessels have dense anastomotic
      networks and are safe to occlude. Symptoms will be evaluated to see if any subside as a
      result of their occlusion. Five minutes after the balloon is deflated, another contrast run
      will be performed to evaluate the caliber of the studied vessel. After this run, the groin
      sheath will be removed and the above protocol will be followed until outpatient follow-up. If
      headache symptoms do not subside, the patient will be administered standard pain medication,
      fentanyl, which is given routinely during angiography at a dose of 25mcg to abate their pain.
      This is a low, tolerable, and safe dose that will be given with the assistance of our
      anesthesia colleagues, if necessary. Their headache pain will be closely monitored during the
      5 hour recovery period, and given 1 more 25mcg dose during this period in order to fully
      subside any pain the patient still may have.

      This angiogram will take approximately 30 minutes to complete, and it is a low risk
      procedure.. The vessels studied diagnostically will be solely extracranial and completely
      separate from intracranial vessels. Any anomalous communication identified between
      extracranial and intracranial vessels will automatically disqualify a patient from
      participation in this study.

      Despite some minor discomfort from the groin puncture for the patient, with the assistance of
      an anesthesiologist the pain intra- and post-procedurally experienced by patients will be
      well controlled. The patient may also opt to receive the rescue pain medication at any time
      during the angiogram and discontinue the study.

      As stated previously, the extracranial vascular circulation has a large anastomotic network
      such that a single vessel sacrifice can be performed without great risk. These vessels are
      sacrificed without sequelae intraoperatively routinely when performing craniotomies. In cases
      where a provocative artery can be found, occlusion of that vessel can lead to improved
      symptoms, as tested by temporary balloon occlusion without great risk. It is the hope that
      this pilot work to guide future interventions to control blood flow in these offending
      vessels, to see if migraines abate permanently with vessel removal from circulation. If these
      hypotheses are correct, interventions may be created to minimize patient's need for
      medication, improve their quality of life, and free them from the debilitation of their
      migraines.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Migraine
time frame: 10 minutes
description: The reporting of migraine-like pain after nitroglycerin administration
measure: Migraine log pre-procedure: severity measure
time frame: 2 weeks
description: Severity of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: frequency measure
time frame: 2 weeks
description: Frequency of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: quality measure
time frame: 2 weeks
description: Quality of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: location measure
time frame: 2 weeks
description: Location of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: alleviating factor measure
time frame: 2 weeks
description: Alleviating factors of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: aggravating factor measure
time frame: 2 weeks
description: Aggravating factors of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: associated symptom measure
time frame: 2 weeks
description: Associated symptoms of migraines for 2 weeks prior to angiogram
measure: Migraine log pre-procedure: therapies utilized measure
time frame: 2 weeks
description: Therapies utilized for migraines for 2 weeks prior to angiogram
measure: Artery dilation
time frame: 10 minutes
description: Enlargement of the diameter of the vessel of interest after nitroglycerin administration
measure: Migraine pain relief
time frame: 20 minutes
description: Relief of induced migraine pain with temporary balloon occlusion of the dilated artery. Standard pain medication will also be available for treatment
measure: Adverse reactions
time frame: 6 hours
description: Monitoring for retroperitoneal hematoma, vascular injury, infection, contrast reaction, worsening contralateral headache symptoms, new neurologic deficit peri-procedurally until discharge
measure: Migraine log follow-up post-procedure: severity measure
time frame: 2 weeks
description: Severity of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: frequency measure
time frame: 2 weeks
description: Frequency of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: quality measure
time frame: 2 weeks
description: Quality of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: location measure
time frame: 2 weeks
description: Location of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: alleviating factors measure
time frame: 2 weeks
description: Alleviating factors of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: aggravating factor measure
time frame: 2 weeks
description: Aggravating factors of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: associated factor measure
time frame: 2 weeks
description: Associated symptoms of migraines for 2 weeks post-angiogram
measure: Migraine log follow-up post-procedure: therapies utilized measure
time frame: 2 weeks
description: Therapies utilized for 2 weeks after angiogram until follow-up clinic visit
arm group label: Migraine Intervention
arm group type: Experimental
description: Subjects who will be administered 200 micrograms of nitroglycerin once into branches of their external carotid artery to determine the role of dilation of this artery to cause migraine-like pain
intervention type: Other
intervention name: Nitroglycerin
description: Intra-arterial adminstration to dilate external carotid artery branches to replicate migraine pain
arm group label: Migraine Intervention
other name: Nitrostat
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: David J Altschul, MD
role: Principal Investigator
affiliation: Montefiore Medical Center
facility: 
country: United States
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PMID: 26917583
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PMID: 19303917
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PMID: 23879550
citation: Evans RW. Diagnostic testing for migraine and other primary headaches. Neurol Clin. 2009 May;27(2):393-415. doi: 10.1016/j.ncl.2008.11.009.
PMID: 19289222
citation: Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study. Brain. 2008 Aug;131(Pt 8):2192-200. doi: 10.1093/brain/awn094. Epub 2008 May 23.
PMID: 18502781
citation: Nagata E, Moriguchi H, Takizawa S, Horie T, Yanagimachi N, Takagi S. The middle meningial artery during a migraine attack: 3T magnetic resonance angiography study. Intern Med. 2009;48(24):2133-5. doi: 10.2169/internalmedicine.48.2565.
PMID: 20009407
citation: Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010 Oct 26;75(17):1520-6. doi: 10.1212/WNL.0b013e3181f9626a.
PMID: 20975053
citation: Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ, Larsson HB, Olesen J, Ashina M. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013 May;12(5):454-61. doi: 10.1016/S1474-4422(13)70067-X. Epub 2013 Apr 9.
PMID: 23578775
citation: Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016 Mar;139(Pt 3):723-37. doi: 10.1093/brain/awv359. Epub 2015 Dec 16.
PMID: 26674653
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PMID: 18789357
citation: Meents JE, Neeb L, Reuter U. TRPV1 in migraine pathophysiology. Trends Mol Med. 2010 Apr;16(4):153-9. doi: 10.1016/j.molmed.2010.02.004. Epub 2010 Mar 27.
PMID: 20347391
citation: Evans MS, Cheng X, Jeffry JA, Disney KE, Premkumar LS. Sumatriptan inhibits TRPV1 channels in trigeminal neurons. Headache. 2012 May;52(5):773-84. doi: 10.1111/j.1526-4610.2011.02053.x. Epub 2012 Jan 30.
PMID: 22289052
citation: Totaro R, De Matteis G, Marini C, Baldassarre M, Carolei A. Sumatriptan and cerebral blood flow velocity changes during migraine attacks. Headache. 1997 Nov-Dec;37(10):635-9. doi: 10.1046/j.1526-4610.1997.3710635.x.
PMID: 9439084
citation: Shevel E. The trigeminovascular system--quo vadis? Headache. 2009 May;49(5):785-6. doi: 10.1111/j.1526-4610.2009.01415.x. No abstract available.
PMID: 19456890
citation: Shevel E. The extracranial vascular theory of migraine: an artificial controversy. J Neural Transm (Vienna). 2011 Apr;118(4):525-30. doi: 10.1007/s00702-010-0517-1. Epub 2011 Jan 5.
PMID: 21207080
citation: Shevel E. The extracranial vascular theory of migraine--a great story confirmed by the facts. Headache. 2011 Mar;51(3):409-417. doi: 10.1111/j.1526-4610.2011.01844.x.
PMID: 21352215
citation: Beekman R, Nijssen PC, van Rooij WJ, Wijnalda D. Migraine with aura after intracranial endovascular procedures. Headache. 2001 Apr;41(4):410-3. doi: 10.1046/j.1526-4610.2001.111006410.x.
PMID: 11318889
citation: Choi KS, Lee JH, Yi HJ, Chun HJ, Lee YJ, Kim DW. Incidence and risk factors of postoperative headache after endovascular coil embolization of unruptured intracranial aneurysms. Acta Neurochir (Wien). 2014 Jul;156(7):1281-7. doi: 10.1007/s00701-014-2095-8. Epub 2014 May 7. Erratum In: Acta Neurochir (Wien). 2014 Sep;156(9):1829.
PMID: 24801821
citation: Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014 Mar;137(Pt 3):779-94. doi: 10.1093/brain/awt369. Epub 2014 Feb 5.
PMID: 24501094
citation: Edvinsson L, Linde M. New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet. 2010 Aug 21;376(9741):645-55. doi: 10.1016/S0140-6736(10)60323-6. Epub 2010 Apr 21.
PMID: 20416945
citation: Meents JE, Hoffmann J, Chaplan SR, Neeb L, Schuh-Hofer S, Wickenden A, Reuter U. Two TRPV1 receptor antagonists are effective in two different experimental models of migraine. J Headache Pain. 2015;16:57. doi: 10.1186/s10194-015-0539-z. Epub 2015 Jun 24.
PMID: 26109436
citation: Hazard E, Munakata J, Bigal ME, Rupnow MF, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value Health. 2009 Jan-Feb;12(1):55-64. doi: 10.1111/j.1524-4733.2008.00404.x. Epub 2008 Jul 30.
PMID: 18671771
citation: Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural changes in the brain: a systematic review and meta-analysis. Neurology. 2013 Oct 1;81(14):1260-8. doi: 10.1212/WNL.0b013e3182a6cb32. Epub 2013 Aug 28.
PMID: 23986301
citation: Starling AJ, Dodick DW. Best practices for patients with chronic migraine: burden, diagnosis, and management in primary care. Mayo Clin Proc. 2015 Mar;90(3):408-14. doi: 10.1016/j.mayocp.2015.01.010.
PMID: 25744118
responsible party type: Principal Investigator
investigator affiliation: Montefiore Medical Center
investigator full name: David Altschul
investigator title: Chief, The Leo M. Davidoff Department of Neurological Surgery Division of Cerebrovascular Neurosurgery
mesh term: Migraine Disorders
mesh term: Migraine without Aura
mesh term: Migraine with Aura
mesh term: Nitroglycerin