<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/NCT04503083</url>
  </required_header>
  <id_info>
    <org_study_id>BIOMIGA2020</org_study_id>
    <nct_id>NCT04503083</nct_id>
  </id_info>
  <brief_title>BIOmarkers of MIGraine: a Proof of Concept Study Based on the Stratification of Responders to CGRP Monoclonal Antibodies</brief_title>
  <acronym>BIOMIGA</acronym>
  <official_title>A Multidisciplinary Approach to the Identification of BIOmarkers of MIGraine: a Proof of Concept Study Based on the Stratification of Responders to CGRP Monoclonal Antibodies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS National Neurological Institute &quot;C. Mondino&quot; Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>IRCCS National Neurological Institute &quot;C. Mondino&quot; Foundation</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Migraine is the 2nd most disabling neurological disease. It affects 14.7% of the population&#xD;
      (children and adults) of whom 80% are female. In the European Union, the total annual cost of&#xD;
      migraine is of 111 billion euros. If not adequately treated, migraine can evolve into the&#xD;
      more severe chronic form (CM), defined by &gt;15 headache days/month, where burden and costs&#xD;
      increase exponentially.&#xD;
&#xD;
      Until very recently, available preventive treatments for migraine were non-specific, of&#xD;
      limited efficacy and scarce tolerability. In 2018, monoclonal antibodies (mABs) against&#xD;
      calcitonin gene-related peptide (CGRP) receptor have been approved. Since CGRP is one of the&#xD;
      main modulators of the trigeminal system, mABs against CGRP are the first specific preventive&#xD;
      treatment for migraine ever developed. They are highly effective in a subgroup of patients,&#xD;
      well tolerated, but costly.&#xD;
&#xD;
      In this frame, the main objective of BIOMIGA project is to identify predictive biomarkers of&#xD;
      response to CGRP-mABs in patients with severe forms of migraine. To this end, the&#xD;
      investigators will use an integrated hypothesis-based and data-driven, multidisciplinary&#xD;
      approach that combines' omic testing in a deep-phenotyped migraine population and parallel&#xD;
      fundamental research in a validated animal model of migraine. Three partners, Headache&#xD;
      Science Centre, IRCCS C. Mondino Foundation, University of Pavia, Italy, Headache Research&#xD;
      Group Vall d'Hebron Institute of Research, Barcelona, Spain and Institut für Systemische&#xD;
      Neurowissenschaften, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany with an&#xD;
      established long-standing and complementary expertise in neuroimaging, biochemical profiling&#xD;
      and epigenetics in humans and in animal modeling of migraine will collaborate to achieve the&#xD;
      Project's objective.&#xD;
&#xD;
      The investigators expect important spin-offs to the improved management of migraine, both in&#xD;
      terms of increased efficacy and cost saving, but also to understand CGRP-based mechanisms&#xD;
      underlying migraine pathophysiology and to set the basis for a pathophysiologically driven&#xD;
      classification. Healthcare providers and the pharmaceutical industry will be engaged once the&#xD;
      biomarker(s) have been identified to optimize access to care and the use of resource, as well&#xD;
      as to reduce disability and socio-economic impact of migraine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Almost 15% of European citizens suffer from migraine and its comorbidities. Migraine is the&#xD;
      second most disabling chronic neurological disease, with devastating repercussions on the&#xD;
      life of those who are affected, their relatives and society. Migraine manifests in recurring&#xD;
      attacks lasting 4-72 hours characterized by severe head pain, often throbbing, associated&#xD;
      with nausea, photo and phonophobia, vomiting, cognitive deficits, severe emotional distress&#xD;
      and complete disability. If not diagnosed and appropriately treated, migraine can transform&#xD;
      into a chronic form (15 or more days of headache/ month) often associated with acute&#xD;
      medication overuse and severe comorbidities such as depression, anxiety and panic disorders.&#xD;
&#xD;
      The disability associated to migraine is closely related to the frequency of the attacks.&#xD;
      Epidemiological studies show that in Europe 34$ of migraineurs suffer from more than 5&#xD;
      headache days per month and 1-3% of the general population has migraine on more than 15&#xD;
      days/month, thus qualifying for the diagnosis of Chronic Migraine (CM).&#xD;
&#xD;
      Migraine is a genetically-driven, chronic &quot;neurosensorial&quot; disorder, where the unpredictable&#xD;
      recurrence of the attacks is modulated by the variable efficiency of the fine-tuned interplay&#xD;
      of the brain with dynamic sensory stimuli originating from the internal or external&#xD;
      environment.&#xD;
&#xD;
      Migraine can be viewed as a cycling functional disorder that affects several areas of the&#xD;
      brain, involving multiple pathways ultimately leading to the excessive activation of&#xD;
      trigeminovascular afferents in the meninges with the local release of vasoactive substances&#xD;
      (calcitonin gene-related peptide - CGRP ) and the activation of the neuroinflammatory&#xD;
      cascade.&#xD;
&#xD;
      Unlike several other chronic neurological diseases, migraine can be successfully treated and&#xD;
      prevented. Unfortunately, this is true only for subgroups of patients and for a limited&#xD;
      period, due to the nonspecific therapeutic armamentarium available: calcium antagonists,&#xD;
      beta-blockers, antidepressants, antiepileptics and, only for chronic migraine,&#xD;
      onabotulinumtoxin-A. This is the direct consequence of the complex pathophysiology of the&#xD;
      disease, but mostly and, more importantly, by the total absence of biomarkers of disease and&#xD;
      of responsiveness to available drugs.&#xD;
&#xD;
      In the last years, enormous efforts have indeed been undertaken to identify biomarker of&#xD;
      migraine, especially for the chronic form. Functional imaging has provided important clues on&#xD;
      the machinery underlying attack generation and imaging biomarkers for chronic migraine,&#xD;
      whereas it has become evident that epigenetic processes - DNA methylation in particular - may&#xD;
      play an important role in the phenotypical expression of migraine. Attack recurrence and the&#xD;
      associated changes in neuronal activity may indeed cause epigenetic changes that alter&#xD;
      synaptic plasticity, thus leading to more frequent migraine attacks and ultimately promotes&#xD;
      stable epigenetic changes in a feed-forward loop. Circulating levels of CGRP have also been&#xD;
      evaluated as a possible peripheral biomarker of migraine in consideration of the seminal&#xD;
      observations that CGRP levels increase in the external jugular vein during a migraine attack.&#xD;
&#xD;
      The second half of 2018 marked a revolution in the treatment of migraine: the advent of the&#xD;
      monoclonal antibodies (mABs) directed against CGRP or its receptor. They proved safe and&#xD;
      effective in reducing migraine frequency and represent the first class of preventive drugs&#xD;
      targeting a specific step in the cascade of events leading to the migraine attack. Results&#xD;
      from clinical trials have shown that approximately 1/3 of patients are excellent responders&#xD;
      (&gt;75% reduction in headache days) whilst 1/3 patients are non- or poor responders (&lt;25%&#xD;
      reduction in headache days) to CGRP-targeted mABs.&#xD;
&#xD;
      CGRP-targeted mABs do not interfere with other systems or medications. Consequently, the fact&#xD;
      that patients can be stratified as responders and non-responders creates a unique opportunity&#xD;
      to better understand the difference of response in patients clinically alike and, through&#xD;
      this, provide unprecedented insights into the pathophysiology of migraine allowing the&#xD;
      migraine field to move towards a pathophysiological driven classification.&#xD;
&#xD;
      For decades the migraine scientific community has been searching for biomarkers associated&#xD;
      with the disease or with its response to treatment. Unfortunately, to date none has been&#xD;
      validated. This failure is likely related to multiple reasons: the complex and dynamic nature&#xD;
      of migraine-associated biological processes (attack vs. pre-post interictal phase), the&#xD;
      multiplicity of neurotransmitters (serotonin dopamine, neuropeptides, etc.), the&#xD;
      neuroanatomical structures (peripheral, central) and the interindividual variability of&#xD;
      disease expression. Moreover, the reasons for the failure of previous studies are also&#xD;
      associated with the variability between studies, in terms of methodology, population and&#xD;
      endpoints, which has led to inconsistent findings and low estimate precision.&#xD;
&#xD;
      Now, a selective class of preventive drugs that specifically target a biological step in&#xD;
      migraine disease has become available, prompting the possibility to precisely stratify&#xD;
      migraine subjects on the basis of their pharmacological response. The availability of&#xD;
      high-throughput technologies is providing unprecedented opportunities to identify molecular&#xD;
      markers of complex disease by extracting meaningful signatures from complex and heterogeneous&#xD;
      sets of data. Molecular biomarkers of thoroughly stratified populations can be combined with&#xD;
      deep clinical phenotyping and also with epigenetic, pharmacogenetic and neuroimaging&#xD;
      variables, that are relevant for migraine. The availability of migraine-specific animal&#xD;
      models also contributes to identifying and firmly placing important pieces to the migraine&#xD;
      puzzle.&#xD;
&#xD;
      Against this background, a hybrid data-driven and knowledge-based approach building on&#xD;
      clinical and preclinical inputs and including phenotype, genetic, neuroimaging and animal&#xD;
      data will provide a large informative dataset that can be effectively analyzed with machine&#xD;
      and deep learning algorithms for feature selection, modeling and for subsequent&#xD;
      cross-validation to ultimately yield a precise, robust and reproducible model for predicting&#xD;
      the response of migraine to a specifically targeted preventive treatment. This will be a&#xD;
      crucial step in the therapeutic decision process, especially in the most severe and disabling&#xD;
      form of migraine, chronic migraine. It will also provide additional positive implications in&#xD;
      the field, such as prompting the ground for a pathophysiology-driven diagnosis and, equally&#xD;
      important, robust scientific evidence to European decision makers and health-care providers&#xD;
      for optimizing the distribution of resources and rationalizing the access to care of migraine&#xD;
      sufferers. Engagement of patients is envisaged both in the planning and conducting of the&#xD;
      study to ensure that project methodology and results are in line with their needs and&#xD;
      expectations, thus favoring the translation into clinical practice.&#xD;
&#xD;
      Monoclonal antibodies targeting CGRP (CGRP-mABs) have been shown to be effective in the&#xD;
      preventive treatment of migraine. They are large molecules that do not cross the blood brain&#xD;
      barrier, have a long half-life (20-45 days) and do not interact pharmacologically. They are&#xD;
      administered parenterally, which warrants less intra-individual variations and a better&#xD;
      adherence to treatment.&#xD;
&#xD;
      CGRP-mABs have proven safe and effective in multiple phase II and III randomized controlled&#xD;
      clinical trials and were approved by FDA and European Medicines Agency (EMA) as a preventive&#xD;
      treatment for migraine. Four CGRP-mABs have been studied and 3 of them have been approved by&#xD;
      EMA in late 2018 and 2019: erenumab, galcanezumab and fremanezumab.&#xD;
&#xD;
      A strong body of evidence suggests that CGRP-mABs induce a 50% response (50% reduction in&#xD;
      monthly headache days) in about 50% of subjects, with a 75% response in 30-40% of patients.&#xD;
      The latter group, from now on defined as 'excellent responders', represents an interesting&#xD;
      subgroup of migraine subjects whose disease is likely particularly dependent on CGRP-related&#xD;
      pathways. Hence, the availability of mABs targeting CGRP together with the demonstration of&#xD;
      their efficacy in relevant subgroups of subjects prompt a formidable tool to tackle precisely&#xD;
      a subset of mechanisms and pathways underlying the disease.&#xD;
&#xD;
      CGRP-targeted mABs do not interfere with other systems or medications. Consequently, the fact&#xD;
      that patients can be precisely stratified as excellent responders and non-responders creates&#xD;
      a unique novel opportunity to unravel hitherto concealed differences between patients with&#xD;
      the same diagnosis and, through this, provides unprecedented insights into the&#xD;
      pathophysiology of migraine. Ultimately, this will allow the migraine field to move towards a&#xD;
      neurobiological definition of responders and a pathophysiological driven classification.&#xD;
      Defining predictors to this response will in turn allow obtaining a more cost-effective&#xD;
      approach to migraine healthcare. Engagement of patients is envisaged both in the planning and&#xD;
      conducting of the study based on the long-standing collaboration with the European Migraine&#xD;
      and Headache Alliance (EMHA), which has been aligned and involved in the preparation of the&#xD;
      present proposal.&#xD;
&#xD;
      Epigenetics is acquiring an increasing importance in the panorama of biological events that&#xD;
      leads to the transformation of episodic migraine (EM) into chronic migraine (CM). Frequent&#xD;
      recurrence of migraine attacks may indeed promote stable epigenetic changes in a feed-forward&#xD;
      loop thus altering synaptic plasticity. So far, the most significant associated CpG sites&#xD;
      related to migraine chronification are SH2D5, NPTX2 and RAMP1, three brain-expressed genes&#xD;
      involved in the regulation of synaptic plasticity and CGRP modulation. However, it is still&#xD;
      not known whether a specific profile of DNA methylation, which is a stable epigenetic&#xD;
      chemical marker crucial for many cellular activities, can predict the clinical response to&#xD;
      preventive therapy in migraine patients.&#xD;
&#xD;
      Neuroimaging Functional imaging studies have revolutionized this area and provided unique&#xD;
      neuroanatomical and functional insights into migraine machinery. Functional imaging has&#xD;
      revealed that the pathophysiology of migraine crucially involves&#xD;
      hypothalamo-thalamo-brainstem networks. Pharmacological imaging has begun to shed light on&#xD;
      how medications may enfold their effect in migraine.&#xD;
&#xD;
      The combination of structural and functional imaging parameters with and without external&#xD;
      input will give us the unique opportunity to characterize patients who respond to&#xD;
      CGRP_targeting antibodies against those who do not. These data will then be an additional&#xD;
      powerful source for informing animal projects and also machine learning algorithms.&#xD;
&#xD;
      The overarching and main objective of this proposal is the identification of predictive&#xD;
      biomarkers of response to treatment with CGRP-targeted mAbs in chronic migraine, the most&#xD;
      severe and disabling form of migraine.&#xD;
&#xD;
      Screening will be performed at visit 1 (month 0). Patients will sign the informed consent and&#xD;
      will be instructed to fill in a headache diary and will return after 1 month (+2 days) for&#xD;
      visit 2 (V2). At V2, after verification of inclusion/exclusion criteria, enrolled subjects&#xD;
      will fill in the protocol scales (Assessment of disability - monthly MIDAS, Headache Impact&#xD;
      Test 6 (HIT-6) -, depression - Beck Depression Inventory, BDI-II -, anxiety - Beck Anxiety&#xD;
      Inventory, Beck Anxiety Inventory (BAI) -, quality of life - MSQ- , subjective cognitive&#xD;
      impairment scale for migraine attacks - Mig-SCog -, comorbidities, acute medications intake,&#xD;
      anxiety and depression - Beck scales - and Emergency Room Use), they will undergo blood&#xD;
      sampling, neuroimaging and they will receive the first treatment administration.&#xD;
&#xD;
      Healthy controls will be screened at V1 and, following the verification of the satisfaction&#xD;
      of inclusion/exclusion criteria and the signature of the informed consent, will fill in the&#xD;
      protocol scale, they will undergo blood sampling and neuroimaging.&#xD;
&#xD;
      The first dose (defined according to the indication approved by the Local Health Authorities)&#xD;
      of the CGRP-targeting monoclonal antibody will be administered during the hospital visit.&#xD;
&#xD;
      The patient will receive 2 additional doses of the drug and a training on the modality of&#xD;
      self-injection and specific indication of the day they will perform the self-injection. They&#xD;
      will also receive the headache diary and associated instructions for filling it in regularly&#xD;
      during the following 3 months.&#xD;
&#xD;
      No drug treatment is foreseen for healthy controls.&#xD;
&#xD;
      No concomitant migraine preventive treatment will be allowed during the screening, baseline&#xD;
      and the 3-month treatment period.&#xD;
&#xD;
      Abortive medications will be allowed, but the type and formulation should be kept stable&#xD;
      during the study. Data about their doses and frequencies will be recorded.&#xD;
&#xD;
      A remote visit will be scheduled 30 (week 4) and 60 (week 8) days after day 1 to monitor&#xD;
      patient's health status, remind the treatment schedule and collect the data from the headache&#xD;
      diaries (visit 3 and 4).&#xD;
&#xD;
      At visit 5 (week 12), all migraine subjects will undergo:&#xD;
&#xD;
        -  Assessment of disability (MIDAS, HIT-6), work impairment (WPAI scale), evaluation of&#xD;
           acute medications intake, anxiety and depression, quality of life (MSQ), Emergency Room&#xD;
           Use.&#xD;
&#xD;
        -  Assessment of treatment efficacy through the headache diaries (migraine days/month)&#xD;
&#xD;
        -  Assessment of treatment satisfaction with validated patient reported outcomes (PROs).&#xD;
&#xD;
      Excellent responders and non-responders will also undergo neuroimaging evaluation: 3Tesla&#xD;
      Magnetic resonance imaging (MRI) involving Structural (sMRI) resting state MRI (rsMRI),&#xD;
      Arterial Spin Labelling (ASL) and Diffusion Tensor Imaging (DTI).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 15, 2021</start_date>
  <completion_date type="Anticipated">March 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Biomarkers and CGRP-targeting mABs</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>To identify a computational algorithm using a machine learning approach based on different types of biomarkers (demographic, clinical, psychological, cognitive, epigenetic, pharmacogenetic, biochemical and structural &amp; functional brain imaging) that is predictive of response to the class of the CGRP-targeting mABs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Methylation levels</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Difference in methylation levels in migraine subjects as compared to healthy controls</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain morphometric measures</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Differences in brain morphometric measures between migraine patients and healthy controls at the neuroanatomic and neurofunctional levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacogenetic, biochemical, clinical and psychological markers</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Differences in pharmacogenetic, biochemical, clinical and psychological markers between migraine patients and healthy controls</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Methylation levels at the neuroanatomic and neurofunctional levels</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Difference in methylation levels in migraine subjects between migraine patients and healthy controls at the neuroanatomic and neurofunctional levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morphometric measures</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Differences in brain morphometric measures between migraine subjects who are responder and those who are non responders to CGRP-targeting mABs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacogenetic, biochemical, clinical and psychological markers in responder and non responders</measure>
    <time_frame>Day 0 and Week 12</time_frame>
    <description>Differences in pharmacogenetic, biochemical, clinical and psychological between migraine subjects who are responder and those who are non responders to CGRP-targeting mABs</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">219</enrollment>
  <condition>Migraine</condition>
  <arm_group>
    <arm_group_label>Migraine patients</arm_group_label>
    <description>Excellent responder, a patient who experiences a &gt;75% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;&#xD;
Responder, a patient who experiences a &gt;50% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;&#xD;
Non responder, a patient who experiences a decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days ranging from 26 to 49% during the last 4 weeks of treatment as compared to baseline;&#xD;
Full non responder, a patient who experiences a &lt;25% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples for DNA extraction for DNA methylation analysis and for CGRP-related&#xD;
      polymorphisms, and for biochemical profiling&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Migraine patients and Healthy controls.&#xD;
&#xD;
        The Health controls will be recruited among hospital staff and non-related acquaintances of&#xD;
        the patients.&#xD;
&#xD;
        All patients enrolled in the study will be treated with CGRP-targeting mABs according to&#xD;
        the indications approved by their National regulatory bodies&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Migraine patients&#xD;
&#xD;
          -  Adults between 25 and 55 years of age of both gender;&#xD;
&#xD;
          -  European background;&#xD;
&#xD;
          -  Patients diagnosed with high-frequency migraine (HFM) 8 or more migraine days&#xD;
             days/month) or CM with or without aura (&gt;15 headache days migraine/month, of which 8&#xD;
             have migraine characteristics) according to the International Classification of&#xD;
             Headache Disorders, 3rd edition, (ICHD-3);&#xD;
&#xD;
          -  Females have to be postmenopausal for at least one year, surgically sterile or&#xD;
             otherwise incapable of pregnancy, or using an acceptable method of birth control.&#xD;
&#xD;
        Healthy controls&#xD;
&#xD;
          -  Adults between 25 and 55 years of age of both genders;&#xD;
&#xD;
          -  European background;&#xD;
&#xD;
          -  Absence of any past or first-degree familial history of recurrent primary or secondary&#xD;
             headache disorders.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        For the clinical population:&#xD;
&#xD;
          -  Headache on more than 25 days/month in the last 3 months;&#xD;
&#xD;
          -  Medication overuse according to the ICHD-3 criteria.&#xD;
&#xD;
        For the entire study population (migraine and healthy controls)&#xD;
&#xD;
          -  Presence of any other significant medical condition (neurological disorders, severe&#xD;
             psychiatric illness or cardiovascular disease);&#xD;
&#xD;
          -  Evidence of drug, smoking or alcohol abuse or dependence within 12 months prior to V1,&#xD;
             based on medical records or patient self-report. An alcohol consumption &gt;100mg/week&#xD;
             will be considered an abuse;&#xD;
&#xD;
          -  Pregnant or breastfeeding women;&#xD;
&#xD;
          -  Women of childbearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant who are not on contraception;&#xD;
&#xD;
          -  Concomitant use of other migraine preventive drugs that may interfere with the&#xD;
             endpoints of the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cristina Tassorelli, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Mondino Foundation, Pavia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cristina Tassorelli, MD</last_name>
    <phone>0039 382 380390</phone>
    <email>cristina.tassorelli@mondino.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Cinzia Fattore, MD</last_name>
    <phone>0039 382385</phone>
    <email>cinzia.fattore@mondino.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Institut für Systemische Neurowissenschaften, Universitätsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20357</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Arne May, MD</last_name>
      <email>a.may@uke.uni-hamburg.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Headache Science Center</name>
      <address>
        <city>Pavia</city>
        <zip>27100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cristina Tassorelli, MD</last_name>
      <phone>0382380390</phone>
      <email>cristina.tassorelli@mondino.it</email>
    </contact>
    <contact_backup>
      <last_name>Daniele Martinelli, MD</last_name>
      <phone>0382 380390</phone>
      <email>daniele.martinelli@mondino.it</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Headache Research Group Vall d'Hebron Institute of Research</name>
      <address>
        <city>Barcelona</city>
        <state>Cataluna</state>
        <zip>8009</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Patricia Pozo-Rosich, MD</last_name>
      <email>ppozorosich@yahoo.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Italy</country>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause of disability in under 50s. J Headache Pain. 2016 Dec;17(1):104. doi: 10.1186/s10194-016-0699-5. Epub 2016 Nov 14. No abstract available.</citation>
    <PMID>27844455</PMID>
  </reference>
  <reference>
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  <verification_date>July 2020</verification_date>
  <study_first_submitted>August 3, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>April 27, 2021</last_update_submitted>
  <last_update_submitted_qc>April 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Migraine</keyword>
  <keyword>Biomarkers</keyword>
  <keyword>CGRP monoclonal Antibodies</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Migraine Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04503083
org study id: BIOMIGA2020
nct id: NCT04503083
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Migraine is the 2nd most disabling neurological disease. It affects 14.7% of the population
      (children and adults) of whom 80% are female. In the European Union, the total annual cost of
      migraine is of 111 billion euros. If not adequately treated, migraine can evolve into the
      more severe chronic form (CM), defined by >15 headache days/month, where burden and costs
      increase exponentially.

      Until very recently, available preventive treatments for migraine were non-specific, of
      limited efficacy and scarce tolerability. In 2018, monoclonal antibodies (mABs) against
      calcitonin gene-related peptide (CGRP) receptor have been approved. Since CGRP is one of the
      main modulators of the trigeminal system, mABs against CGRP are the first specific preventive
      treatment for migraine ever developed. They are highly effective in a subgroup of patients,
      well tolerated, but costly.

      In this frame, the main objective of BIOMIGA project is to identify predictive biomarkers of
      response to CGRP-mABs in patients with severe forms of migraine. To this end, the
      investigators will use an integrated hypothesis-based and data-driven, multidisciplinary
      approach that combines' omic testing in a deep-phenotyped migraine population and parallel
      fundamental research in a validated animal model of migraine. Three partners, Headache
      Science Centre, IRCCS C. Mondino Foundation, University of Pavia, Italy, Headache Research
      Group Vall d'Hebron Institute of Research, Barcelona, Spain and Institut für Systemische
      Neurowissenschaften, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany with an
      established long-standing and complementary expertise in neuroimaging, biochemical profiling
      and epigenetics in humans and in animal modeling of migraine will collaborate to achieve the
      Project's objective.

      The investigators expect important spin-offs to the improved management of migraine, both in
      terms of increased efficacy and cost saving, but also to understand CGRP-based mechanisms
      underlying migraine pathophysiology and to set the basis for a pathophysiologically driven
      classification. Healthcare providers and the pharmaceutical industry will be engaged once the
      biomarker(s) have been identified to optimize access to care and the use of resource, as well
      as to reduce disability and socio-economic impact of migraine.
Almost 15% of European citizens suffer from migraine and its comorbidities. Migraine is the
      second most disabling chronic neurological disease, with devastating repercussions on the
      life of those who are affected, their relatives and society. Migraine manifests in recurring
      attacks lasting 4-72 hours characterized by severe head pain, often throbbing, associated
      with nausea, photo and phonophobia, vomiting, cognitive deficits, severe emotional distress
      and complete disability. If not diagnosed and appropriately treated, migraine can transform
      into a chronic form (15 or more days of headache/ month) often associated with acute
      medication overuse and severe comorbidities such as depression, anxiety and panic disorders.

      The disability associated to migraine is closely related to the frequency of the attacks.
      Epidemiological studies show that in Europe 34$ of migraineurs suffer from more than 5
      headache days per month and 1-3% of the general population has migraine on more than 15
      days/month, thus qualifying for the diagnosis of Chronic Migraine (CM).

      Migraine is a genetically-driven, chronic "neurosensorial" disorder, where the unpredictable
      recurrence of the attacks is modulated by the variable efficiency of the fine-tuned interplay
      of the brain with dynamic sensory stimuli originating from the internal or external
      environment.

      Migraine can be viewed as a cycling functional disorder that affects several areas of the
      brain, involving multiple pathways ultimately leading to the excessive activation of
      trigeminovascular afferents in the meninges with the local release of vasoactive substances
      (calcitonin gene-related peptide - CGRP ) and the activation of the neuroinflammatory
      cascade.

      Unlike several other chronic neurological diseases, migraine can be successfully treated and
      prevented. Unfortunately, this is true only for subgroups of patients and for a limited
      period, due to the nonspecific therapeutic armamentarium available: calcium antagonists,
      beta-blockers, antidepressants, antiepileptics and, only for chronic migraine,
      onabotulinumtoxin-A. This is the direct consequence of the complex pathophysiology of the
      disease, but mostly and, more importantly, by the total absence of biomarkers of disease and
      of responsiveness to available drugs.

      In the last years, enormous efforts have indeed been undertaken to identify biomarker of
      migraine, especially for the chronic form. Functional imaging has provided important clues on
      the machinery underlying attack generation and imaging biomarkers for chronic migraine,
      whereas it has become evident that epigenetic processes - DNA methylation in particular - may
      play an important role in the phenotypical expression of migraine. Attack recurrence and the
      associated changes in neuronal activity may indeed cause epigenetic changes that alter
      synaptic plasticity, thus leading to more frequent migraine attacks and ultimately promotes
      stable epigenetic changes in a feed-forward loop. Circulating levels of CGRP have also been
      evaluated as a possible peripheral biomarker of migraine in consideration of the seminal
      observations that CGRP levels increase in the external jugular vein during a migraine attack.

      The second half of 2018 marked a revolution in the treatment of migraine: the advent of the
      monoclonal antibodies (mABs) directed against CGRP or its receptor. They proved safe and
      effective in reducing migraine frequency and represent the first class of preventive drugs
      targeting a specific step in the cascade of events leading to the migraine attack. Results
      from clinical trials have shown that approximately 1/3 of patients are excellent responders
      (>75% reduction in headache days) whilst 1/3 patients are non- or poor responders (<25%
      reduction in headache days) to CGRP-targeted mABs.

      CGRP-targeted mABs do not interfere with other systems or medications. Consequently, the fact
      that patients can be stratified as responders and non-responders creates a unique opportunity
      to better understand the difference of response in patients clinically alike and, through
      this, provide unprecedented insights into the pathophysiology of migraine allowing the
      migraine field to move towards a pathophysiological driven classification.

      For decades the migraine scientific community has been searching for biomarkers associated
      with the disease or with its response to treatment. Unfortunately, to date none has been
      validated. This failure is likely related to multiple reasons: the complex and dynamic nature
      of migraine-associated biological processes (attack vs. pre-post interictal phase), the
      multiplicity of neurotransmitters (serotonin dopamine, neuropeptides, etc.), the
      neuroanatomical structures (peripheral, central) and the interindividual variability of
      disease expression. Moreover, the reasons for the failure of previous studies are also
      associated with the variability between studies, in terms of methodology, population and
      endpoints, which has led to inconsistent findings and low estimate precision.

      Now, a selective class of preventive drugs that specifically target a biological step in
      migraine disease has become available, prompting the possibility to precisely stratify
      migraine subjects on the basis of their pharmacological response. The availability of
      high-throughput technologies is providing unprecedented opportunities to identify molecular
      markers of complex disease by extracting meaningful signatures from complex and heterogeneous
      sets of data. Molecular biomarkers of thoroughly stratified populations can be combined with
      deep clinical phenotyping and also with epigenetic, pharmacogenetic and neuroimaging
      variables, that are relevant for migraine. The availability of migraine-specific animal
      models also contributes to identifying and firmly placing important pieces to the migraine
      puzzle.

      Against this background, a hybrid data-driven and knowledge-based approach building on
      clinical and preclinical inputs and including phenotype, genetic, neuroimaging and animal
      data will provide a large informative dataset that can be effectively analyzed with machine
      and deep learning algorithms for feature selection, modeling and for subsequent
      cross-validation to ultimately yield a precise, robust and reproducible model for predicting
      the response of migraine to a specifically targeted preventive treatment. This will be a
      crucial step in the therapeutic decision process, especially in the most severe and disabling
      form of migraine, chronic migraine. It will also provide additional positive implications in
      the field, such as prompting the ground for a pathophysiology-driven diagnosis and, equally
      important, robust scientific evidence to European decision makers and health-care providers
      for optimizing the distribution of resources and rationalizing the access to care of migraine
      sufferers. Engagement of patients is envisaged both in the planning and conducting of the
      study to ensure that project methodology and results are in line with their needs and
      expectations, thus favoring the translation into clinical practice.

      Monoclonal antibodies targeting CGRP (CGRP-mABs) have been shown to be effective in the
      preventive treatment of migraine. They are large molecules that do not cross the blood brain
      barrier, have a long half-life (20-45 days) and do not interact pharmacologically. They are
      administered parenterally, which warrants less intra-individual variations and a better
      adherence to treatment.

      CGRP-mABs have proven safe and effective in multiple phase II and III randomized controlled
      clinical trials and were approved by FDA and European Medicines Agency (EMA) as a preventive
      treatment for migraine. Four CGRP-mABs have been studied and 3 of them have been approved by
      EMA in late 2018 and 2019: erenumab, galcanezumab and fremanezumab.

      A strong body of evidence suggests that CGRP-mABs induce a 50% response (50% reduction in
      monthly headache days) in about 50% of subjects, with a 75% response in 30-40% of patients.
      The latter group, from now on defined as 'excellent responders', represents an interesting
      subgroup of migraine subjects whose disease is likely particularly dependent on CGRP-related
      pathways. Hence, the availability of mABs targeting CGRP together with the demonstration of
      their efficacy in relevant subgroups of subjects prompt a formidable tool to tackle precisely
      a subset of mechanisms and pathways underlying the disease.

      CGRP-targeted mABs do not interfere with other systems or medications. Consequently, the fact
      that patients can be precisely stratified as excellent responders and non-responders creates
      a unique novel opportunity to unravel hitherto concealed differences between patients with
      the same diagnosis and, through this, provides unprecedented insights into the
      pathophysiology of migraine. Ultimately, this will allow the migraine field to move towards a
      neurobiological definition of responders and a pathophysiological driven classification.
      Defining predictors to this response will in turn allow obtaining a more cost-effective
      approach to migraine healthcare. Engagement of patients is envisaged both in the planning and
      conducting of the study based on the long-standing collaboration with the European Migraine
      and Headache Alliance (EMHA), which has been aligned and involved in the preparation of the
      present proposal.

      Epigenetics is acquiring an increasing importance in the panorama of biological events that
      leads to the transformation of episodic migraine (EM) into chronic migraine (CM). Frequent
      recurrence of migraine attacks may indeed promote stable epigenetic changes in a feed-forward
      loop thus altering synaptic plasticity. So far, the most significant associated CpG sites
      related to migraine chronification are SH2D5, NPTX2 and RAMP1, three brain-expressed genes
      involved in the regulation of synaptic plasticity and CGRP modulation. However, it is still
      not known whether a specific profile of DNA methylation, which is a stable epigenetic
      chemical marker crucial for many cellular activities, can predict the clinical response to
      preventive therapy in migraine patients.

      Neuroimaging Functional imaging studies have revolutionized this area and provided unique
      neuroanatomical and functional insights into migraine machinery. Functional imaging has
      revealed that the pathophysiology of migraine crucially involves
      hypothalamo-thalamo-brainstem networks. Pharmacological imaging has begun to shed light on
      how medications may enfold their effect in migraine.

      The combination of structural and functional imaging parameters with and without external
      input will give us the unique opportunity to characterize patients who respond to
      CGRP_targeting antibodies against those who do not. These data will then be an additional
      powerful source for informing animal projects and also machine learning algorithms.

      The overarching and main objective of this proposal is the identification of predictive
      biomarkers of response to treatment with CGRP-targeted mAbs in chronic migraine, the most
      severe and disabling form of migraine.

      Screening will be performed at visit 1 (month 0). Patients will sign the informed consent and
      will be instructed to fill in a headache diary and will return after 1 month (+2 days) for
      visit 2 (V2). At V2, after verification of inclusion/exclusion criteria, enrolled subjects
      will fill in the protocol scales (Assessment of disability - monthly MIDAS, Headache Impact
      Test 6 (HIT-6) -, depression - Beck Depression Inventory, BDI-II -, anxiety - Beck Anxiety
      Inventory, Beck Anxiety Inventory (BAI) -, quality of life - MSQ- , subjective cognitive
      impairment scale for migraine attacks - Mig-SCog -, comorbidities, acute medications intake,
      anxiety and depression - Beck scales - and Emergency Room Use), they will undergo blood
      sampling, neuroimaging and they will receive the first treatment administration.

      Healthy controls will be screened at V1 and, following the verification of the satisfaction
      of inclusion/exclusion criteria and the signature of the informed consent, will fill in the
      protocol scale, they will undergo blood sampling and neuroimaging.

      The first dose (defined according to the indication approved by the Local Health Authorities)
      of the CGRP-targeting monoclonal antibody will be administered during the hospital visit.

      The patient will receive 2 additional doses of the drug and a training on the modality of
      self-injection and specific indication of the day they will perform the self-injection. They
      will also receive the headache diary and associated instructions for filling it in regularly
      during the following 3 months.

      No drug treatment is foreseen for healthy controls.

      No concomitant migraine preventive treatment will be allowed during the screening, baseline
      and the 3-month treatment period.

      Abortive medications will be allowed, but the type and formulation should be kept stable
      during the study. Data about their doses and frequencies will be recorded.

      A remote visit will be scheduled 30 (week 4) and 60 (week 8) days after day 1 to monitor
      patient's health status, remind the treatment schedule and collect the data from the headache
      diaries (visit 3 and 4).

      At visit 5 (week 12), all migraine subjects will undergo:

        -  Assessment of disability (MIDAS, HIT-6), work impairment (WPAI scale), evaluation of
           acute medications intake, anxiety and depression, quality of life (MSQ), Emergency Room
           Use.

        -  Assessment of treatment efficacy through the headache diaries (migraine days/month)

        -  Assessment of treatment satisfaction with validated patient reported outcomes (PROs).

      Excellent responders and non-responders will also undergo neuroimaging evaluation: 3Tesla
      Magnetic resonance imaging (MRI) involving Structural (sMRI) resting state MRI (rsMRI),
      Arterial Spin Labelling (ASL) and Diffusion Tensor Imaging (DTI).
observational model: Cohort
time perspective: Prospective
measure: Biomarkers and CGRP-targeting mABs
time frame: Day 0 and Week 12
description: To identify a computational algorithm using a machine learning approach based on different types of biomarkers (demographic, clinical, psychological, cognitive, epigenetic, pharmacogenetic, biochemical and structural & functional brain imaging) that is predictive of response to the class of the CGRP-targeting mABs.
measure: Methylation levels
time frame: Day 0 and Week 12
description: Difference in methylation levels in migraine subjects as compared to healthy controls
measure: Brain morphometric measures
time frame: Day 0 and Week 12
description: Differences in brain morphometric measures between migraine patients and healthy controls at the neuroanatomic and neurofunctional levels
measure: Pharmacogenetic, biochemical, clinical and psychological markers
time frame: Day 0 and Week 12
description: Differences in pharmacogenetic, biochemical, clinical and psychological markers between migraine patients and healthy controls
measure: Methylation levels at the neuroanatomic and neurofunctional levels
time frame: Day 0 and Week 12
description: Difference in methylation levels in migraine subjects between migraine patients and healthy controls at the neuroanatomic and neurofunctional levels
measure: Morphometric measures
time frame: Day 0 and Week 12
description: Differences in brain morphometric measures between migraine subjects who are responder and those who are non responders to CGRP-targeting mABs
measure: Pharmacogenetic, biochemical, clinical and psychological markers in responder and non responders
time frame: Day 0 and Week 12
description: Differences in pharmacogenetic, biochemical, clinical and psychological between migraine subjects who are responder and those who are non responders to CGRP-targeting mABs
arm group label: Migraine patients
description: Excellent responder, a patient who experiences a >75% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;
Responder, a patient who experiences a >50% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline;
Non responder, a patient who experiences a decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days ranging from 26 to 49% during the last 4 weeks of treatment as compared to baseline;
Full non responder, a patient who experiences a <25% decrease of either the monthly number of migraine days or the monthly number of moderate/severe headache days during the last 4 weeks of treatment as compared to baseline.
Blood samples for DNA extraction for DNA methylation analysis and for CGRP-related
      polymorphisms, and for biochemical profiling
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 25 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Cristina Tassorelli, Prof
role: Principal Investigator
affiliation: IRCCS Mondino Foundation, Pavia
last name: Cristina Tassorelli, MD
phone: 0039 382 380390
email: cristina.tassorelli@mondino.it
last name: Cinzia Fattore, MD
phone: 0039 382385
email: cinzia.fattore@mondino.it
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Not yet recruiting
contact: 
country: Germany
country: Italy
country: Spain
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responsible party type: Sponsor
mesh term: Migraine Disorders
sharing ipd: No