<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/NCT03244709</url>
  </required_header>
  <id_info>
    <org_study_id>Hospital of Prato, Italy</org_study_id>
    <nct_id>NCT03244709</nct_id>
  </id_info>
  <brief_title>Tocilizumab Dose-tapering and Interruption in Patients With Giant Cell Arteritis Achieving the Clinical Remission.</brief_title>
  <official_title>Tocilizumab Dose-tapering and Interruption in Patients With Giant Cell Arteritis Achieving the Clinical Remission: a Prospective, Pilot Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital of Prato</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital of Prato</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been found to have a crucial role in&#xD;
      the pathogenesis of Giant cel arteritis (GCA). Based on this rationale, several recent&#xD;
      studies demonstrated the efficacy of tocilizumab (TCZ), an anti-IL-6 targeted monoclonal&#xD;
      antibody, for the treatment of patients with refractory GCA. Confirming previous reports,in a&#xD;
      recent retrospective study the investigators successfully treated 10 patient with refractory&#xD;
      GCA with TCZ. All patients achieved a complete disease remission evaluated by clinical,&#xD;
      laboratory, and positron emission tomography (PET). In a considerable number of GCA patients&#xD;
      treated with corticosteroids (CS) the therapy may be interrupted with no disease flares. No&#xD;
      data are available on the management of patients achieving the remission with TCZ.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design. Open-label, prospective, pilot study on patients with giant cell arteritis&#xD;
      (GCA) resistant to corticosteroids (CS) .&#xD;
&#xD;
      Setting. Rheumatology department, Hospital of Prato, Prato, Italy. Treatment. All refractory&#xD;
      GCA patients with or without involvement of aorta and its thoracic branches treated with&#xD;
      intravenous TCZ at the dose of 8 mg/Kg/monthly or subcutaneous TCZ at the dose of 162&#xD;
      mg/weekly who achieved a stable remission over a 6-month period should receive reduced TCZ&#xD;
      doses with the following schedules: intravenous TCZ tapering to 2 mg/Kg/monthly with drug&#xD;
      withdrawal at month 4, and subcutaneous TCZ monthly reduction through the lengthening of&#xD;
      injection intervals every 2, 3 , and 4 weeks, and with drug interruption at month 4.&#xD;
&#xD;
      Primary end-point. To investigate the maintenance of clinical remission after TCZ&#xD;
      interruption over a 6-month follow-up period.&#xD;
&#xD;
      Secondary end-points. To assess the maintenance of clinical remission during the treatment,&#xD;
      to evaluate the role of acute-phase reactants and PET in predicting the relapse and&#xD;
      remission, and to assess the occurrence of adverse event (AEs).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 1, 2015</start_date>
  <completion_date type="Anticipated">December 31, 2017</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The percentage of patients maintaining the off-therapy clinical remission over the follow-up as expressed by absence of GCA symptoms and signs, normal ESR and CRP values, absence of arterial wall inflammation at PET examination</measure>
    <time_frame>6-month off-therapy period</time_frame>
    <description>ESR ≤15 mm/h; CRP ≤0.5 mg/dl; VAS pain ≤10; PET: normalized SUVmax ≤1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The percentage of patients achieving and maintaining the clinical remission during the treatment with TCZ as expressed by the absence of GCA symptoms and signs, normal ESR and CRP values, absence of arterial wall inflammation at PET examination</measure>
    <time_frame>12 months</time_frame>
    <description>Absence of GCA symptoms and signs, ESR ≤15 mm/h, CRP ≤0.5 mg/dL, PET: normalized SUVmax ≤1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To compare the role of acute-phase reactants and 18F-FDG-PET in the evaluation of remission.</measure>
    <time_frame>Months 6,12,18</time_frame>
    <description>Linear regression analysis for the correlation between ESR and CRP values and nSUVmax at baseline and after therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0&quot; MeDRA 12.1.</measure>
    <time_frame>Month 18</time_frame>
    <description>Overall AEs and serious AEs will be recorded</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Giant Cell Arteritis</condition>
  <arm_group>
    <arm_group_label>Patients with GCA (ACR 1990 criteria)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At diagnosis, all GCA patients with or without involvement of aorta and its thoracic branches will receive PDN 50 mg/day and TCZ 8 mg/Kg/iv monthly. In all patients PDN dose will be reduced of 10 mg every 2 weeks until interruption at week 12.&#xD;
Week 12. Subcutaneous TCZ 162 mg/weekly will be administered for additional 12 weeks.&#xD;
Week 24. TCZ tapering every 8 weeks as follows:&#xD;
1 injection every 2 weeks&#xD;
1 injection every 3 weeks&#xD;
1 injection every 4 weeks Week 48. TCZ withdrawal. Week 72. Remission evaluation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Intravenous Tocilizumab followed by subcutaneousTocilizumab</description>
    <arm_group_label>Patients with GCA (ACR 1990 criteria)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - All consecutive patients meeting the 1990 ACR classification criteria for GCA.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Corticosteroid treatment during the previous 6 months.&#xD;
&#xD;
          -  Uncontrolled diabetes.&#xD;
&#xD;
          -  Uncontrolled hypertension.&#xD;
&#xD;
          -  History of cancer within the past 5 years.&#xD;
&#xD;
          -  History of frequent infections in the past.&#xD;
&#xD;
          -  Positivity of screening procedures for latent tuberculosis infection.&#xD;
&#xD;
          -  Uncontrolled dyslipidemia at baseline.&#xD;
&#xD;
          -  Known intestinal diverticulosis.&#xD;
&#xD;
          -  Concomitant hematologic disorders.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Fabrizio Cantini</name>
      <address>
        <city>Prato</city>
        <state>Tuscany</state>
        <zip>59100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Fabrizio Cantini, MD</last_name>
      <phone>+393408075607</phone>
      <email>fbrzcantini@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Carlotta Nannini, MD</last_name>
      <phone>+390574807578</phone>
      <email>nannini.car@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008 Jul 19;372(9634):234-45. doi: 10.1016/S0140-6736(08)61077-6.</citation>
    <PMID>18640460</PMID>
  </reference>
  <reference>
    <citation>Soussan M, Nicolas P, Schramm C, Katsahian S, Pop G, Fain O, Mekinian A. Management of large-vessel vasculitis with FDG-PET: a systematic literature review and meta-analysis. Medicine (Baltimore). 2015 Apr;94(14):e622. doi: 10.1097/MD.0000000000000622.</citation>
    <PMID>25860208</PMID>
  </reference>
  <reference>
    <citation>Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 Jul 27;377(4):317-328. doi: 10.1056/NEJMoa1613849.</citation>
    <PMID>28745999</PMID>
  </reference>
  <results_reference>
    <citation>Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, Stone JR, Stone JH. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012 Nov;64(11):1720-9. doi: 10.1002/acr.21750.</citation>
    <PMID>22674883</PMID>
  </results_reference>
  <results_reference>
    <citation>Loricera J, Blanco R, Hernandez JL, Castaneda S, Mera A, Perez-Pampin E, Peiro E, Humbria A, Calvo-Alen J, Aurrecoechea E, Narvaez J, Sanchez-Andrade A, Vela P, Diez E, Mata C, Lluch P, Moll C, Hernandez I, Calvo-Rio V, Ortiz-Sanjuan F, Gonzalez-Vela C, Pina T, Gonzalez-Gay MA. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015 Jun;44(6):717-23. doi: 10.1016/j.semarthrit.2014.12.005. Epub 2014 Dec 27.</citation>
    <PMID>25697557</PMID>
  </results_reference>
  <results_reference>
    <citation>Proven A, Gabriel SE, Orces C, O'Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum. 2003 Oct 15;49(5):703-8. doi: 10.1002/art.11388.</citation>
    <PMID>14558057</PMID>
  </results_reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>August 9, 2017</last_update_submitted>
  <last_update_submitted_qc>August 9, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 10, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital of Prato</investigator_affiliation>
    <investigator_full_name>Fabrizio Cantini</investigator_full_name>
    <investigator_title>Director of the Dpt. of Rheumatology</investigator_title>
  </responsible_party>
  <keyword>Giant cell arteritis,</keyword>
  <keyword>Tocilizumab</keyword>
  <keyword>Aortitis</keyword>
  <keyword>Remission</keyword>
  <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>
  <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/NCT03244709
org study id: Hospital of Prato, Italy
nct id: NCT03244709
lead sponsor: 
has dmc: No
Interleukin-6 (IL-6), a pro-inflammatory cytokine, has been found to have a crucial role in
      the pathogenesis of Giant cel arteritis (GCA). Based on this rationale, several recent
      studies demonstrated the efficacy of tocilizumab (TCZ), an anti-IL-6 targeted monoclonal
      antibody, for the treatment of patients with refractory GCA. Confirming previous reports,in a
      recent retrospective study the investigators successfully treated 10 patient with refractory
      GCA with TCZ. All patients achieved a complete disease remission evaluated by clinical,
      laboratory, and positron emission tomography (PET). In a considerable number of GCA patients
      treated with corticosteroids (CS) the therapy may be interrupted with no disease flares. No
      data are available on the management of patients achieving the remission with TCZ.
Study design. Open-label, prospective, pilot study on patients with giant cell arteritis
      (GCA) resistant to corticosteroids (CS) .

      Setting. Rheumatology department, Hospital of Prato, Prato, Italy. Treatment. All refractory
      GCA patients with or without involvement of aorta and its thoracic branches treated with
      intravenous TCZ at the dose of 8 mg/Kg/monthly or subcutaneous TCZ at the dose of 162
      mg/weekly who achieved a stable remission over a 6-month period should receive reduced TCZ
      doses with the following schedules: intravenous TCZ tapering to 2 mg/Kg/monthly with drug
      withdrawal at month 4, and subcutaneous TCZ monthly reduction through the lengthening of
      injection intervals every 2, 3 , and 4 weeks, and with drug interruption at month 4.

      Primary end-point. To investigate the maintenance of clinical remission after TCZ
      interruption over a 6-month follow-up period.

      Secondary end-points. To assess the maintenance of clinical remission during the treatment,
      to evaluate the role of acute-phase reactants and PET in predicting the relapse and
      remission, and to assess the occurrence of adverse event (AEs).
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The percentage of patients maintaining the off-therapy clinical remission over the follow-up as expressed by absence of GCA symptoms and signs, normal ESR and CRP values, absence of arterial wall inflammation at PET examination
time frame: 6-month off-therapy period
description: ESR ≤15 mm/h; CRP ≤0.5 mg/dl; VAS pain ≤10; PET: normalized SUVmax ≤1
measure: The percentage of patients achieving and maintaining the clinical remission during the treatment with TCZ as expressed by the absence of GCA symptoms and signs, normal ESR and CRP values, absence of arterial wall inflammation at PET examination
time frame: 12 months
description: Absence of GCA symptoms and signs, ESR ≤15 mm/h, CRP ≤0.5 mg/dL, PET: normalized SUVmax ≤1
measure: To compare the role of acute-phase reactants and 18F-FDG-PET in the evaluation of remission.
time frame: Months 6,12,18
description: Linear regression analysis for the correlation between ESR and CRP values and nSUVmax at baseline and after therapy
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0" MeDRA 12.1.
time frame: Month 18
description: Overall AEs and serious AEs will be recorded
arm group label: Patients with GCA (ACR 1990 criteria)
arm group type: Experimental
description: At diagnosis, all GCA patients with or without involvement of aorta and its thoracic branches will receive PDN 50 mg/day and TCZ 8 mg/Kg/iv monthly. In all patients PDN dose will be reduced of 10 mg every 2 weeks until interruption at week 12.
Week 12. Subcutaneous TCZ 162 mg/weekly will be administered for additional 12 weeks.
Week 24. TCZ tapering every 8 weeks as follows:
1 injection every 2 weeks
1 injection every 3 weeks
1 injection every 4 weeks Week 48. TCZ withdrawal. Week 72. Remission evaluation.
intervention type: Drug
intervention name: Tocilizumab
description: Intravenous Tocilizumab followed by subcutaneousTocilizumab
arm group label: Patients with GCA (ACR 1990 criteria)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
country: Italy
citation: Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008 Jul 19;372(9634):234-45. doi: 10.1016/S0140-6736(08)61077-6.
PMID: 18640460
citation: Soussan M, Nicolas P, Schramm C, Katsahian S, Pop G, Fain O, Mekinian A. Management of large-vessel vasculitis with FDG-PET: a systematic literature review and meta-analysis. Medicine (Baltimore). 2015 Apr;94(14):e622. doi: 10.1097/MD.0000000000000622.
PMID: 25860208
citation: Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 Jul 27;377(4):317-328. doi: 10.1056/NEJMoa1613849.
PMID: 28745999
citation: Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, Stone JR, Stone JH. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken). 2012 Nov;64(11):1720-9. doi: 10.1002/acr.21750.
PMID: 22674883
citation: Loricera J, Blanco R, Hernandez JL, Castaneda S, Mera A, Perez-Pampin E, Peiro E, Humbria A, Calvo-Alen J, Aurrecoechea E, Narvaez J, Sanchez-Andrade A, Vela P, Diez E, Mata C, Lluch P, Moll C, Hernandez I, Calvo-Rio V, Ortiz-Sanjuan F, Gonzalez-Vela C, Pina T, Gonzalez-Gay MA. Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015 Jun;44(6):717-23. doi: 10.1016/j.semarthrit.2014.12.005. Epub 2014 Dec 27.
PMID: 25697557
citation: Proven A, Gabriel SE, Orces C, O'Fallon WM, Hunder GG. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum. 2003 Oct 15;49(5):703-8. doi: 10.1002/art.11388.
PMID: 14558057
responsible party type: Principal Investigator
investigator affiliation: Hospital of Prato
investigator full name: Fabrizio Cantini
investigator title: Director of the Dpt. of Rheumatology
mesh term: Polymyalgia Rheumatica
mesh term: Giant Cell Arteritis
mesh term: Arteritis
sharing ipd: No