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/NCT06037460</url>
    </required_header>
    <id_info>
      <org_study_id>SAMSON PHRCN 2021</org_study_id>
      <nct_id>NCT06037460</nct_id>
    </id_info>
    <brief_title>TocilizuMab discontinuAtion in GIant Cell Arteritis</brief_title>
    <acronym>MAGICA</acronym>
    <official_title>TocilizuMab discontinuAtion in GIant Cell Arteritis</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Centre Hospitalier Universitaire Dijon</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Centre Hospitalier Universitaire Dijon</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Giant cell arteritis (GCA) is a large-vessel vasculitis that typically occurs in people over&#xD;
        the age of 50.&#xD;
  &#xD;
        Corticosteroids (GC) are the cornerstone of treatment for GCA. French guidelines recommend&#xD;
        starting at 0.7 or 1 mg/kg/day at diagnosis, depending on the occurence of ischemic&#xD;
        complication(s). Then, it is recommended to gradually decrease their dose to achieve&#xD;
        withdrawal in 12 to 24 months.&#xD;
  &#xD;
        Despite this treatment, 47% of patients relapse. Relapses are favored by rapid reduction of&#xD;
        corticosteroid doses and large vessel involvement at diagnosis. Fortunately, relapses are&#xD;
        severe in only 3.3% of cases and ischemic complications are very rare. However, this&#xD;
        contributes to prolonging the duration of corticosteroid treatment and thus the risk of&#xD;
        cortico-induced adverse events, which have not been significantly reduced in the last 20&#xD;
        years. The main risk factors for the development of steroid-related complications are&#xD;
        advanced age and cumulative steroid dose.&#xD;
  &#xD;
        For this reason, the development of cortisone-sparing strategies is necessary to improve the&#xD;
        management of patients with GCA. Thanks to major advances in the understanding of the&#xD;
        pathophysiological mechanisms of GCA, new therapeutic targets have been discovered. For&#xD;
        example, the efficacy of tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, has&#xD;
        been demonstrated in two phase 2 trials and one phase 3 trial, leading to its approval for&#xD;
        the management of patients requiring rapid reduction in corticosteroid doses and/or those&#xD;
        relapsing repeatedly on prednisone &gt;7.5 mg/day. In recently published US guidelines, TCZ can&#xD;
        even be used at diagnosis to reduce the need for corticosteroid therapy.5 Indeed, TCZ appears&#xD;
        to be remarkably effective in controlling GCA activity and saves approximately 2000 mg of&#xD;
        prednisone in cumulative dose.&#xD;
  &#xD;
        At present, the place of TCZ compared to methotrexate in the therapeutic strategy is still&#xD;
        being evaluated, notably through the METOGiA study (PHRC-N 2017), which is being conducted by&#xD;
        our team. Inclusions for METOGiA ended in March 2023 with results expected in 2025. Outside&#xD;
        of this study, approximately 1500 patients are currently receiving TCZ treatment for GCA&#xD;
        (data from ROCHE-CHUGAI).&#xD;
  &#xD;
        There is no doubt that TCZ treatment is effective and rather well tolerated in the elderly&#xD;
        population, but it generates problems that are not solved to date:&#xD;
  &#xD;
          -  the cost (~900€/month)&#xD;
  &#xD;
          -  the difficulty monitoring these patients because the biological markers usually used to&#xD;
             monitor GCA (CRP, ESR, fibrinogen) can no longer be measured since TCZ blocks their&#xD;
             production by the hepatocytes. Monitoring of disease activity therefore requires very&#xD;
             careful clinical examination and the use of expensive imaging tests such as PET scans&#xD;
             because GCA can be active despite normal ESR, CRP and fibrinogen levels. Some studies&#xD;
             suggest that monitoring serum IL-6 may help identify patients with active disease, but&#xD;
             this test is not readily available and the threshold above which relapse should be&#xD;
             suspected is unclear because TCZ induces an increase in serum IL-6 levels by blocking&#xD;
             IL-6 receptors, even in patients in remission.&#xD;
  &#xD;
          -  For the same reasons, infections are difficult to detect in patients treated with TCZ.&#xD;
  &#xD;
        This raises the question of how to discontinue this treatment, especially since other&#xD;
        treatments that do not interfere with CRP, ESR, or fibrinogen measurements are being&#xD;
        evaluated.&#xD;
  &#xD;
        This shows that this treatment tends to be prolonged well beyond one year when the disease is&#xD;
        often in remission without corticosteroids. This is probably related to two factors: 1/ the&#xD;
        fear of relapse after treatment withdrawal; 2/ the absence of a scheme for withdrawing TCZ.&#xD;
  &#xD;
        The risk of relapse after stopping TCZ has been reported in several studies, in particular&#xD;
        the long-term follow-up of phase 2 and 3 trials that demonstrated the efficacy of TCZ for the&#xD;
        treatment of GCA. Overall, regardless of the duration of TCZ treatment, the risk of relapse&#xD;
        is approximately 40% 6 months after the last injection of TCZ, and the risk of relapse is&#xD;
        higher if the large arteries (aorta and its branches) are involved.&#xD;
  &#xD;
        Thus, although the available data are limited, it appears that tapering rather than&#xD;
        immediately stopping TCZ limits the risk of relapse after full withdrawal.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">January 2024</start_date>
    <completion_date type="Anticipated">July 2028</completion_date>
    <primary_completion_date type="Anticipated">August 2027</primary_completion_date>
    <phase>Phase 3</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>The relapse-free survival in both groups (immediate vs. gradual discontinuation)</measure>
      <time_frame>at 26 weeks of follow-up</time_frame>
      <description>The relapse-free survival in both groups (immediate vs. gradual discontinuation) defined as the time from S0 (start of immediate/progressive discontinuation strategy) to relapse or death (any cause), whichever occurs first.</description>
    </primary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Giant Cell Arteritis</condition>
    <arm_group>
      <arm_group_label>Gradual discontinuation of TCZ</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <arm_group>
      <arm_group_label>Immediate discontinuation of TCZ</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Tocilizumab treatment</intervention_name>
      <description>1 injection/2 weeks from W0 to W12: W0, W2, W4, W6, W8, W10, W12&#xD;
  Then 1 injection/4 weeks until W24: W16, W20, W24</description>
      <arm_group_label>Gradual discontinuation of TCZ</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>questionnaires</intervention_name>
      <description>HAQ, SF-36, FACIT-Fatigue score</description>
      <arm_group_label>Gradual discontinuation of TCZ</arm_group_label>
      <arm_group_label>Immediate discontinuation of TCZ</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Blood samples</intervention_name>
      <description>Additionnal blood samples for immunomonitoring</description>
      <arm_group_label>Gradual discontinuation of TCZ</arm_group_label>
      <arm_group_label>Immediate discontinuation of TCZ</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Procedure</intervention_type>
      <intervention_name>18FDG PET scan</intervention_name>
      <description>PETVAS calculation (to be performed between W0 and W8) (optional).</description>
      <arm_group_label>Gradual discontinuation of TCZ</arm_group_label>
      <arm_group_label>Immediate discontinuation of TCZ</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Written consent&#xD;
  &#xD;
            -  Diagnosis of GCA, defined by the following criteria:&#xD;
  &#xD;
                 -  Age ≥50 years at diagnosis&#xD;
  &#xD;
                 -  AND History of ESR ≥50 mm/h OR CRP ≥20 mg/L (optional criterion if temporal&#xD;
                    artery biopsy (TAB) is positive).&#xD;
  &#xD;
                 -  AND at least one of the following clinical criteria:&#xD;
  &#xD;
                      -  At least one unequivocal sign of GCA (recent headache, scalp hyperesthesia,&#xD;
                         jaw claudication, temporal artery abnormality, visual disturbances of&#xD;
                         ischemic origin)&#xD;
  &#xD;
                      -  Clinical sign(s) of polymyalgia rheumatica (PR)&#xD;
  &#xD;
                 -  AND at least one of the following criteria during GCA follow-up:&#xD;
  &#xD;
                      -  TAB consistent with the diagnosis of GCA (non-necrotizing vasculitis with a&#xD;
                         mononuclear cell-rich inflammatory infiltrate or presence of granulomas,&#xD;
                         with or without multinuclear giant cells)&#xD;
  &#xD;
                      -  Evidence of temporal artery vasculitis by echo-Doppler of the temporal&#xD;
                         arteries (unilateral or bilateral halo sign)&#xD;
  &#xD;
                      -  Evidence of vasculitis of at least one large vessel by imaging:&#xD;
  &#xD;
                 -  angio-CT or angio-MRI: arterial wall thickening (≥2mm for aorta; ≥1mm for&#xD;
                    supra-aortic trunks and upper extremity arteries) and/or T1-weighted contrast.&#xD;
  &#xD;
                 -  PET: grade 2 or 3* hypermetabolism of the wall of at least one large vessel&#xD;
                    (aorta, supra-aortic trunks, cephalic vessels, upper extremity arteries) (*i.e.,&#xD;
                    arterial SUVmax ≥ liver SUVmax)&#xD;
  &#xD;
            -  GCA in remission for at least 12 weeks (remission = absence of symptoms due to GCA AND&#xD;
               CRP ≤10 mg/L)&#xD;
  &#xD;
            -  TCZ treatment (IV or SC) or biosimilar initiated 12 to 36 months prior to&#xD;
               randomization&#xD;
  &#xD;
            -  TCZ treatment (IV or SC) or biosimilar not interrupted more than 12 weeks in the 12&#xD;
               months prior to randomization&#xD;
  &#xD;
            -  Treatment with subcutaneous TCZ (162 mg/week) or biosimilar for at least 12&#xD;
               consecutive weeks prior to randomization&#xD;
  &#xD;
            -  Treatment with corticoids stopped at least 12 weeks before randomization&#xD;
               (hydrocortisone treatment ≤20 mg/day is possible if given at a stable dose for the&#xD;
               duration of the study)&#xD;
  &#xD;
            -  Biological workup dating from less than 6 weeks on the day of randomization, showing&#xD;
               good tolerance of tocilizumab:&#xD;
  &#xD;
                 -  AST and ALT &lt; 1.5 x upper limit of normal (ULN)&#xD;
  &#xD;
                 -  Hemoglobin &gt;8 g/dL&#xD;
  &#xD;
                 -  Platelets &gt;100 G/L&#xD;
  &#xD;
                 -  Neutrophils &gt;1 G/L&#xD;
  &#xD;
                 -  Lymphocytes &gt;0.5 G/L&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Person who is not affiliated with the national health insurance system&#xD;
  &#xD;
            -  Person subject to a measure of legal protection (guardianship, tutorship)&#xD;
  &#xD;
            -  Person subject to a court order&#xD;
  &#xD;
            -  Patient unable to give consent&#xD;
  &#xD;
            -  Person who does not speak French&#xD;
  &#xD;
            -  Pre-menopausal women (menopause = amenorrhea of more than 12 consecutive months)&#xD;
  &#xD;
            -  Uncontrolled psychotic state&#xD;
  &#xD;
            -  History of drug or alcohol intoxication requiring hospitalization within 12 months&#xD;
               prior to randomization&#xD;
  &#xD;
            -  Recent or scheduled surgery within 6 months of randomization&#xD;
  &#xD;
            -  History of organ or hematopoietic marrow transplantation (except corneal&#xD;
               transplantation performed at least 12 weeks prior to randomization)&#xD;
  &#xD;
            -  Primary or secondary immune deficiency&#xD;
  &#xD;
            -  Concomitant treatment with any of the following:&#xD;
  &#xD;
                 -  Methotrexate, leflunomide, cyclosporin A, azathioprine, mycophenolate mofetil,&#xD;
                    Janus kinase inhibitors, abatacept, secukinumab, anti-TNF-α, anakinra,&#xD;
                    ustekinumab, or any other immunosuppressive drug within 12 weeks prior to&#xD;
                    randomization&#xD;
  &#xD;
                 -  Rituximab or other anti-CD20 agent within 1 year prior to randomization&#xD;
  &#xD;
                 -  Cyclophosphamide in the year prior to randomization&#xD;
  &#xD;
            -  History of long-term corticosteroid therapy for conditions other than GCA or PPR. (NB:&#xD;
               dermocorticoids, inhaled corticosteroids, and corticosteroid joint infiltrations are&#xD;
               allowed during the study)&#xD;
  &#xD;
            -  Patient who has previously received ≥3 courses of oral corticosteroids for a disease&#xD;
               other than GCA or RRP within 6 months prior to randomization&#xD;
  &#xD;
            -  Ongoing anti-tuberculosis treatment at the time of randomization&#xD;
  &#xD;
            -  Infections:&#xD;
  &#xD;
                 -  Current viral hepatitis B or C&#xD;
  &#xD;
                 -  Ongoing HIV infection&#xD;
  &#xD;
                 -  Severe infection requiring hospitalization within 30 days prior to randomization&#xD;
  &#xD;
            -  Any unstable or poorly controlled condition or disease, acute or chronic, not related&#xD;
               to GCA, and considered a contraindication to tocilizumab therapy in the opinion of the&#xD;
               investigator&#xD;
  &#xD;
            -  Neoplasia &lt; 5 years, (except cervical cancer in situ and skin carcinoma, except&#xD;
               melanoma, with R0 resection)&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>51 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Maxime SAMSON</last_name>
      <phone>0380293432</phone>
      <phone_ext>+33</phone_ext>
      <email>maxime.samson@chu-dijon.fr</email>
    </overall_contact>
    <location>
      <facility>
        <name>Chu Dijon Bourgogne</name>
        <address>
          <city>Dijon</city>
          <zip>21000</zip>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Maxime SAMSON</last_name>
        <phone>0380293432</phone>
        <phone_ext>+33</phone_ext>
        <email>maxime.samson@chu-dijon.fr</email>
      </contact>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 7, 2023</study_first_submitted>
    <study_first_submitted_qc>September 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 14, 2023</study_first_posted>
    <last_update_submitted>September 7, 2023</last_update_submitted>
    <last_update_submitted_qc>September 7, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Polymyalgia Rheumatica</mesh_term>
      <mesh_term>Giant Cell Arteritis</mesh_term>
      <mesh_term>Arteritis</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Fluorodeoxyglucose F18</mesh_term>
    </intervention_browse>
    <!-- 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/NCT06037460
  org study id: SAMSON PHRCN 2021
  nct id: NCT06037460
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  Giant cell arteritis (GCA) is a large-vessel vasculitis that typically occurs in people over
        the age of 50.
  
        Corticosteroids (GC) are the cornerstone of treatment for GCA. French guidelines recommend
        starting at 0.7 or 1 mg/kg/day at diagnosis, depending on the occurence of ischemic
        complication(s). Then, it is recommended to gradually decrease their dose to achieve
        withdrawal in 12 to 24 months.
  
        Despite this treatment, 47% of patients relapse. Relapses are favored by rapid reduction of
        corticosteroid doses and large vessel involvement at diagnosis. Fortunately, relapses are
        severe in only 3.3% of cases and ischemic complications are very rare. However, this
        contributes to prolonging the duration of corticosteroid treatment and thus the risk of
        cortico-induced adverse events, which have not been significantly reduced in the last 20
        years. The main risk factors for the development of steroid-related complications are
        advanced age and cumulative steroid dose.
  
        For this reason, the development of cortisone-sparing strategies is necessary to improve the
        management of patients with GCA. Thanks to major advances in the understanding of the
        pathophysiological mechanisms of GCA, new therapeutic targets have been discovered. For
        example, the efficacy of tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, has
        been demonstrated in two phase 2 trials and one phase 3 trial, leading to its approval for
        the management of patients requiring rapid reduction in corticosteroid doses and/or those
        relapsing repeatedly on prednisone >7.5 mg/day. In recently published US guidelines, TCZ can
        even be used at diagnosis to reduce the need for corticosteroid therapy.5 Indeed, TCZ appears
        to be remarkably effective in controlling GCA activity and saves approximately 2000 mg of
        prednisone in cumulative dose.
  
        At present, the place of TCZ compared to methotrexate in the therapeutic strategy is still
        being evaluated, notably through the METOGiA study (PHRC-N 2017), which is being conducted by
        our team. Inclusions for METOGiA ended in March 2023 with results expected in 2025. Outside
        of this study, approximately 1500 patients are currently receiving TCZ treatment for GCA
        (data from ROCHE-CHUGAI).
  
        There is no doubt that TCZ treatment is effective and rather well tolerated in the elderly
        population, but it generates problems that are not solved to date:
  
          -  the cost (~900€/month)
  
          -  the difficulty monitoring these patients because the biological markers usually used to
             monitor GCA (CRP, ESR, fibrinogen) can no longer be measured since TCZ blocks their
             production by the hepatocytes. Monitoring of disease activity therefore requires very
             careful clinical examination and the use of expensive imaging tests such as PET scans
             because GCA can be active despite normal ESR, CRP and fibrinogen levels. Some studies
             suggest that monitoring serum IL-6 may help identify patients with active disease, but
             this test is not readily available and the threshold above which relapse should be
             suspected is unclear because TCZ induces an increase in serum IL-6 levels by blocking
             IL-6 receptors, even in patients in remission.
  
          -  For the same reasons, infections are difficult to detect in patients treated with TCZ.
  
        This raises the question of how to discontinue this treatment, especially since other
        treatments that do not interfere with CRP, ESR, or fibrinogen measurements are being
        evaluated.
  
        This shows that this treatment tends to be prolonged well beyond one year when the disease is
        often in remission without corticosteroids. This is probably related to two factors: 1/ the
        fear of relapse after treatment withdrawal; 2/ the absence of a scheme for withdrawing TCZ.
  
        The risk of relapse after stopping TCZ has been reported in several studies, in particular
        the long-term follow-up of phase 2 and 3 trials that demonstrated the efficacy of TCZ for the
        treatment of GCA. Overall, regardless of the duration of TCZ treatment, the risk of relapse
        is approximately 40% 6 months after the last injection of TCZ, and the risk of relapse is
        higher if the large arteries (aorta and its branches) are involved.
  
        Thus, although the available data are limited, it appears that tapering rather than
        immediately stopping TCZ limits the risk of relapse after full withdrawal.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: The relapse-free survival in both groups (immediate vs. gradual discontinuation)
  time frame: at 26 weeks of follow-up
  description: The relapse-free survival in both groups (immediate vs. gradual discontinuation) defined as the time from S0 (start of immediate/progressive discontinuation strategy) to relapse or death (any cause), whichever occurs first.
  arm group label: Gradual discontinuation of TCZ
  arm group type: Experimental
  arm group label: Immediate discontinuation of TCZ
  arm group type: Active Comparator
  intervention type: Drug
  intervention name: Tocilizumab treatment
  description: 1 injection/2 weeks from W0 to W12: W0, W2, W4, W6, W8, W10, W12
  Then 1 injection/4 weeks until W24: W16, W20, W24
  arm group label: Gradual discontinuation of TCZ
  intervention type: Other
  intervention name: questionnaires
  description: HAQ, SF-36, FACIT-Fatigue score
  arm group label: Gradual discontinuation of TCZ
  arm group label: Immediate discontinuation of TCZ
  intervention type: Biological
  intervention name: Blood samples
  description: Additionnal blood samples for immunomonitoring
  arm group label: Gradual discontinuation of TCZ
  arm group label: Immediate discontinuation of TCZ
  intervention type: Procedure
  intervention name: 18FDG PET scan
  description: PETVAS calculation (to be performed between W0 and W8) (optional).
  arm group label: Gradual discontinuation of TCZ
  arm group label: Immediate discontinuation of TCZ
  criteria: 
  gender: All
  minimum age: 51 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Maxime SAMSON
  phone: 0380293432
  phone ext: +33
  email: maxime.samson@chu-dijon.fr
  facility: 
  contact: 
  country: France
  responsible party type: Sponsor
  mesh term: Polymyalgia Rheumatica
  mesh term: Giant Cell Arteritis
  mesh term: Arteritis
  mesh term: Fluorodeoxyglucose F18