xml: <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/NCT06035458</url>
    </required_header>
    <id_info>
      <org_study_id>EOCNSIHA_2201</org_study_id>
      <nct_id>NCT06035458</nct_id>
    </id_info>
    <brief_title>Potential Osteocatabolic Effect Caused by Anti-CGRP mAbs in Migraine Patients Treated With Anti-CGRP mAbs - an Observational Pilot Project With Prospectively Collected Health Related Data</brief_title>
    <official_title>Potential Osteocatabolic Effect Caused by Anti-CGRP mAbs in Migraine Patients Treated With Anti-CGRP mAbs - an Observational Pilot Project With Prospectively Collected Health Related Data</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Ente Ospedaliero Cantonale, Bellinzona</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Ente Ospedaliero Cantonale, Bellinzona</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>
        Background: To gain insight on the osteoanabolic activity of anti-CGRP mAbs in patients with&#xD;
        migraine as this was not yet specifically investigated in registration or post-approval&#xD;
        clinical studies, however, being pathophysiologically plausible. If a clinically relevant,&#xD;
        osteocatabolic effect caused by anti-CGRP mAbs will be demonstrated by the present&#xD;
        investigation monitoring and mitigating strategies might be required and addressed in&#xD;
        dedicated future studies. Objectives: To investigate whether treatment with anti-CGRP mAbs&#xD;
        over 6, 12, and 24 months is associated with changes in bone density, structure and/or&#xD;
        metabolic turnover in migraine patients.&#xD;
  &#xD;
        Project Design and Procedures: Prospective collection of health-related clinical data, open&#xD;
        label, controlled pilot study. Demographic (ethnicity, age, sex) and physical (age, height)&#xD;
        data, data on medical and migraine history will be collected. Clinical procedures include&#xD;
        bone mineral measurement (bone densitometry, dxa) performed according to clinical practice;&#xD;
        venipunctures for laboratory assessments (haematology and blood chemistry; bone turnover&#xD;
        biomarkers P1NP and CTX).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Migraine is a chronic and often lifelong disease defined by recurrent unprovoked headache&#xD;
        episodes lasting over four hours with one or more disabling symptoms including nausea,&#xD;
        vomiting, dizziness, and extreme sensitivity to sound and light. It directly affects more&#xD;
        than 1 billion people worldwide, representing the most common neurological condition with an&#xD;
        estimated 1-year prevalence of 15%. It is approximately twice as high in females compared to&#xD;
        males [5]. In individuals younger than 50 years, migraine represents the leading cause of&#xD;
        years lived with disability worldwide [6], and a major public health concern, as it is&#xD;
        insufficiently recognized leading to considerable individual and societal costs [7]. The&#xD;
        current migraine treatment armamentarium available includes acute and preventive medications,&#xD;
        as well as non-pharmacological approaches. Preventive therapies used until recently were just&#xD;
        non-specific medications such as beta-blockers, calcium channel antagonists, antidepressants,&#xD;
        and antiepileptic drugs, which are often limited by insufficient efficacy and/or relevant&#xD;
        short and long-term side effects [8]. More recently, anti-calcitonin gene related peptide&#xD;
        (CGRP) monoclonal antibodies (mAbs) have been approved as pharmacological preventive&#xD;
        therapies for migraine and currently represent game changer in the field. CGRP, a 37-residue&#xD;
        neuropeptide produced in specific neurons by alternative splicing of the calcitonin gene,&#xD;
        acts as a potent vasodilator as well as a neurotransmitter [9]. In humans, CGRP is present in&#xD;
        two isoforms, α-CGRP and β-CGRP. α-CGRP is the principal isoform localized in the peripheral&#xD;
        and central sensory nervous system [10], and plays a key role in the underlying mechanism of&#xD;
        migraine, as illustrated by several lines of preclinical and human evidence. Intravenous&#xD;
        infusion of this neuropeptide elicits vasodilatation and precipitates migraine attacks in&#xD;
        subjects diagnosed with migraine [11, 12]. Additionally, an increase in plasma CGRP&#xD;
        concentrations can be measured in the craniovascular circulation during migraine attacks&#xD;
        [13]. At the trigeminocervical complex, CGRP also plays a crucial role in central&#xD;
        sensitization, a critical step in the development of migraine headache [14]. Accordingly,&#xD;
        blockade of the CGRPergic transmission has become attractive for the development of targeted&#xD;
        and highly effective migraine treatment strategies. These include mAbs binding CGRP&#xD;
        (galcanezumab, fremanezumab, eptinezumab), or its receptor (CGRPR; erenumab). When used as&#xD;
        preventive therapies in patients with episodic or chronic migraine, these new antimigraine&#xD;
        mAbs (anti-CGRP mAbs) showed effectiveness in reducing the frequency and intensity of attacks&#xD;
        and as well as migraine associated symptoms. Anti- CGRP mAbs were well-tolerated and safe&#xD;
        according to pivotal trials [15-24] and their open label extensions up to 5 years [25]. The&#xD;
        most frequent adverse events reported in these studies were nasopharyngitis, upper&#xD;
        respiratory tract infections, nausea, arthralgia, fatigue, and injection site pain, however&#xD;
        these did not generally exceed rates observed in placebo treatment arms [26]. However,&#xD;
        patients included in registration clinical trials may differ from those treated in the&#xD;
        clinical practice, since the former are typically limited in number, younger, and with a low&#xD;
        burden of comorbidities and concomitant medications. Consequently, the adverse event profile&#xD;
        of a given drug can significantly differ in these two contexts, underlining the importance of&#xD;
        post-marketing surveillance and 'real world' observational studies. According to that, in&#xD;
        clinical trials the administration of anti-CGRP mAbs did not produce significant&#xD;
        cardiovascular side effects, which represented a concern since CGRP is a potent physiological&#xD;
        vasodilator widely represented in the human body [15-24]. Instead, the first-inclass mAb&#xD;
        erenumab was recently found to be associated with an increased risk of new onset or worsening&#xD;
        arterial hypertension[27] , which has now been included among warnings in the the erenumab&#xD;
        label by FDA [28]. Based on the wide distribution of CGRP and its receptor in the body,&#xD;
        additional off-target effects might be also expected when anti-CGRP mAbs are used extensively&#xD;
        in the clinical practice. Besides the cardiovascular system, the CGRP/CGRP receptor system is&#xD;
        actually present in the central and peripheral nervous system (particularly, the blood brain&#xD;
        barrier, the anterior pituitary, the pineal gland, and the area postrema), gastrointestinal&#xD;
        and vestibular system, the kidney and the skin, and has a role in the endocrinal system and&#xD;
        bone metabolism [29]. The objective of this study is to investigate whether treatment with&#xD;
        anti-CGRP mAbs over 6, 12, and 24 months is associated with changes in bone density,&#xD;
        structure and/or metabolic turnover in migraine patients.&#xD;
  &#xD;
        We hypothesize that the continuous use of anti-CGRP mAbs causes bone reabsorption, which in&#xD;
        turn reflects in increased bone catabolic biomarkers, decreased bone anabolic biomarkers and&#xD;
        ultimately in reduced bone density (BMD) and altered trabecular structure (TMS).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">April 13, 2022</start_date>
    <completion_date type="Anticipated">March 31, 2024</completion_date>
    <primary_completion_date type="Anticipated">March 31, 2024</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>Changes in bone mineral density</measure>
      <time_frame>6-12 months</time_frame>
      <description>Change in lumbar spine, total hip and femoral neck bone mineral density and lumbar spine TBS during anti-CGRP mAb.</description>
    </primary_outcome>
    <enrollment type="Anticipated">42</enrollment>
    <condition>Migraine Disorders</condition>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Diagnostic radiology</intervention_name>
      <description>Clinical procedures include bone mineral measurement (bone densitometry, dxa) performed according to clinical practice; venipunctures for laboratory assessments (haematology and blood chemistry; bone turnover biomarkers P1NP and CTX).</description>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          Patients who present with migraine at the Headache out-patient clinic, Neurocenter of&#xD;
          Southern Switzerland, EOC, will be recruited during routine clinical evaluations. At our&#xD;
          Headache Clinic, migraine patients planned to start an anti-CGRP mAb undergo a preliminary&#xD;
          screening to identify those suffering from or at increased risk of osteoporosis/osteopenia.&#xD;
  &#xD;
          Patients not planned to start an anti-CGRP mAb will be screened to match a treated patient&#xD;
          for age and sex.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          Anti-CGRP mAbs treated group (TC):&#xD;
  &#xD;
            -  Anti-CGRP mAbs naïve males and females;&#xD;
  &#xD;
            -  Aged between 18 and 50 years;&#xD;
  &#xD;
            -  Affected with migraine with or without aura [4];&#xD;
  &#xD;
            -  Planning to start a migraine preventive monotherapy with and satisfying the&#xD;
               prescription criteria for Anti-CGRP mAbs erenumab, galcanezumab, and fremanezumab&#xD;
               according to the Swiss reimbursement authorities (previous treatment with at least 2&#xD;
               migraine preventive therapies among beta-blockers, calcium antagonists,&#xD;
               anticonvulsants and selective serotonin reuptake inhibitors SSRI must have been&#xD;
               ineffective, contraindicated or not tolerated; mean number of monthly migraine days&#xD;
               (MMD) in three consecutive months must be at least 8).&#xD;
  &#xD;
          Control group, not treated with anti-CGRP mAbs (CG)&#xD;
  &#xD;
            -  Males and females&#xD;
  &#xD;
            -  Aged between 18 and 50 years;&#xD;
  &#xD;
            -  Affected with migraine with or without aura [4];&#xD;
  &#xD;
            -  Under no migraine preventive therapies;&#xD;
  &#xD;
            -  Never treated with / not planning to start on anti-CGRP mAbs&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  An ongoing treatment with one of the following drugs: protonic pump inhibitors,&#xD;
               selective serotonin reuptake inhibitors (such as escitalopram, fluoxetine, paroxetine,&#xD;
               sertraline), glitazones, anti-aromatase, anti-androgen medications, glucocorticoids;&#xD;
               having ever received glucocorticoids at doses of ≥5 mg (or equivalent) for ≥3 months,&#xD;
               anti-retroviral drugs, vitamin k inhibitors or bone antiresorptive therapy;&#xD;
  &#xD;
                 -  An ongoing supplementation with calcium, vitamin D;&#xD;
  &#xD;
                 -  Being affected with osteoporosis or previous unprovoked fractures at adult age;&#xD;
  &#xD;
                 -  Being affected with significant comorbidities potentially interfering with bone&#xD;
                    metabolism including: type 1 or 2 diabetes; gastrointestinal malabsorption and/or&#xD;
                    chronic inflammatory bowel diseases; primary hyperparathyroidism;&#xD;
                    hyperthyroidism; prolonged immobilization; rheumatoid arthritis; chronic&#xD;
                    obstructive bronchopneumopathy; Cushing syndrome; any other relevant diseases&#xD;
                    according to the investigator's judgement;&#xD;
  &#xD;
                 -  A history of drug or alcohol abuse, or illicit substances use;&#xD;
  &#xD;
                 -  Hypogonadism;&#xD;
  &#xD;
                 -  Menopause;&#xD;
  &#xD;
                 -  Pregnancy or breastfeeding.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>50 Years</maximum_age>
    </eligibility>
    <overall_contact>
      <last_name>Chiara ZECCA, Prof, MD</last_name>
      <phone>+41918116688</phone>
      <email>chiara.zecca@eoc.ch</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Rosaria Sacco, MD, PhD</last_name>
      <phone>+41918116688</phone>
      <email>rosaria.sacco@eoc.ch</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Chiara ZECCA</name>
        <address>
          <city>Lugano</city>
          <state>Ticino</state>
          <zip>6903</zip>
          <country>Switzerland</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Chiara ZECCA, Prof, MD</last_name>
        <phone>+41918116688</phone>
        <email>chiara.zecca@eoc.ch</email>
      </contact>
      <contact_backup>
        <last_name>Rosaria Sacco, MD, PhD</last_name>
        <phone>+41918116688</phone>
        <email>rosaria.sacco@eoc.ch</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Switzerland</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 6, 2023</study_first_submitted>
    <study_first_submitted_qc>September 6, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 6, 2023</last_update_submitted>
    <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Ente Ospedaliero Cantonale, Bellinzona</investigator_affiliation>
      <investigator_full_name>Chiara Zecca</investigator_full_name>
      <investigator_title>Prof</investigator_title>
    </responsible_party>
    <keyword>Migraine</keyword>
    <keyword>anti-CGRP mAb</keyword>
    <keyword>Densitometry</keyword>
    <keyword>osteocatabolic effect</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>
  
  
text: 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/NCT06035458
  org study id: EOCNSIHA_2201
  nct id: NCT06035458
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Background: To gain insight on the osteoanabolic activity of anti-CGRP mAbs in patients with
        migraine as this was not yet specifically investigated in registration or post-approval
        clinical studies, however, being pathophysiologically plausible. If a clinically relevant,
        osteocatabolic effect caused by anti-CGRP mAbs will be demonstrated by the present
        investigation monitoring and mitigating strategies might be required and addressed in
        dedicated future studies. Objectives: To investigate whether treatment with anti-CGRP mAbs
        over 6, 12, and 24 months is associated with changes in bone density, structure and/or
        metabolic turnover in migraine patients.
  
        Project Design and Procedures: Prospective collection of health-related clinical data, open
        label, controlled pilot study. Demographic (ethnicity, age, sex) and physical (age, height)
        data, data on medical and migraine history will be collected. Clinical procedures include
        bone mineral measurement (bone densitometry, dxa) performed according to clinical practice;
        venipunctures for laboratory assessments (haematology and blood chemistry; bone turnover
        biomarkers P1NP and CTX).
  Migraine is a chronic and often lifelong disease defined by recurrent unprovoked headache
        episodes lasting over four hours with one or more disabling symptoms including nausea,
        vomiting, dizziness, and extreme sensitivity to sound and light. It directly affects more
        than 1 billion people worldwide, representing the most common neurological condition with an
        estimated 1-year prevalence of 15%. It is approximately twice as high in females compared to
        males [5]. In individuals younger than 50 years, migraine represents the leading cause of
        years lived with disability worldwide [6], and a major public health concern, as it is
        insufficiently recognized leading to considerable individual and societal costs [7]. The
        current migraine treatment armamentarium available includes acute and preventive medications,
        as well as non-pharmacological approaches. Preventive therapies used until recently were just
        non-specific medications such as beta-blockers, calcium channel antagonists, antidepressants,
        and antiepileptic drugs, which are often limited by insufficient efficacy and/or relevant
        short and long-term side effects [8]. More recently, anti-calcitonin gene related peptide
        (CGRP) monoclonal antibodies (mAbs) have been approved as pharmacological preventive
        therapies for migraine and currently represent game changer in the field. CGRP, a 37-residue
        neuropeptide produced in specific neurons by alternative splicing of the calcitonin gene,
        acts as a potent vasodilator as well as a neurotransmitter [9]. In humans, CGRP is present in
        two isoforms, α-CGRP and β-CGRP. α-CGRP is the principal isoform localized in the peripheral
        and central sensory nervous system [10], and plays a key role in the underlying mechanism of
        migraine, as illustrated by several lines of preclinical and human evidence. Intravenous
        infusion of this neuropeptide elicits vasodilatation and precipitates migraine attacks in
        subjects diagnosed with migraine [11, 12]. Additionally, an increase in plasma CGRP
        concentrations can be measured in the craniovascular circulation during migraine attacks
        [13]. At the trigeminocervical complex, CGRP also plays a crucial role in central
        sensitization, a critical step in the development of migraine headache [14]. Accordingly,
        blockade of the CGRPergic transmission has become attractive for the development of targeted
        and highly effective migraine treatment strategies. These include mAbs binding CGRP
        (galcanezumab, fremanezumab, eptinezumab), or its receptor (CGRPR; erenumab). When used as
        preventive therapies in patients with episodic or chronic migraine, these new antimigraine
        mAbs (anti-CGRP mAbs) showed effectiveness in reducing the frequency and intensity of attacks
        and as well as migraine associated symptoms. Anti- CGRP mAbs were well-tolerated and safe
        according to pivotal trials [15-24] and their open label extensions up to 5 years [25]. The
        most frequent adverse events reported in these studies were nasopharyngitis, upper
        respiratory tract infections, nausea, arthralgia, fatigue, and injection site pain, however
        these did not generally exceed rates observed in placebo treatment arms [26]. However,
        patients included in registration clinical trials may differ from those treated in the
        clinical practice, since the former are typically limited in number, younger, and with a low
        burden of comorbidities and concomitant medications. Consequently, the adverse event profile
        of a given drug can significantly differ in these two contexts, underlining the importance of
        post-marketing surveillance and 'real world' observational studies. According to that, in
        clinical trials the administration of anti-CGRP mAbs did not produce significant
        cardiovascular side effects, which represented a concern since CGRP is a potent physiological
        vasodilator widely represented in the human body [15-24]. Instead, the first-inclass mAb
        erenumab was recently found to be associated with an increased risk of new onset or worsening
        arterial hypertension[27] , which has now been included among warnings in the the erenumab
        label by FDA [28]. Based on the wide distribution of CGRP and its receptor in the body,
        additional off-target effects might be also expected when anti-CGRP mAbs are used extensively
        in the clinical practice. Besides the cardiovascular system, the CGRP/CGRP receptor system is
        actually present in the central and peripheral nervous system (particularly, the blood brain
        barrier, the anterior pituitary, the pineal gland, and the area postrema), gastrointestinal
        and vestibular system, the kidney and the skin, and has a role in the endocrinal system and
        bone metabolism [29]. The objective of this study is to investigate whether treatment with
        anti-CGRP mAbs over 6, 12, and 24 months is associated with changes in bone density,
        structure and/or metabolic turnover in migraine patients.
  
        We hypothesize that the continuous use of anti-CGRP mAbs causes bone reabsorption, which in
        turn reflects in increased bone catabolic biomarkers, decreased bone anabolic biomarkers and
        ultimately in reduced bone density (BMD) and altered trabecular structure (TMS).
  observational model: Cohort
  time perspective: Prospective
  measure: Changes in bone mineral density
  time frame: 6-12 months
  description: Change in lumbar spine, total hip and femoral neck bone mineral density and lumbar spine TBS during anti-CGRP mAb.
  intervention type: Diagnostic Test
  intervention name: Diagnostic radiology
  description: Clinical procedures include bone mineral measurement (bone densitometry, dxa) performed according to clinical practice; venipunctures for laboratory assessments (haematology and blood chemistry; bone turnover biomarkers P1NP and CTX).
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 50 Years
  last name: Chiara ZECCA, Prof, MD
  phone: +41918116688
  email: chiara.zecca@eoc.ch
  last name: Rosaria Sacco, MD, PhD
  phone: +41918116688
  email: rosaria.sacco@eoc.ch
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Switzerland
  responsible party type: Principal Investigator
  investigator affiliation: Ente Ospedaliero Cantonale, Bellinzona
  investigator full name: Chiara Zecca
  investigator title: Prof
  mesh term: Migraine Disorders
  sharing ipd: No