<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/NCT03254589</url>
  </required_header>
  <id_info>
    <org_study_id>HREC/17/SAC/46</org_study_id>
    <nct_id>NCT03254589</nct_id>
  </id_info>
  <brief_title>Methotrexate, Blood Pressure and Arterial Function in Rheumatoid Arthritis</brief_title>
  <official_title>Methotrexate, Blood Pressure and Arterial Function in Rheumatoid Arthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Flinders University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of South Australia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>medac GmbH</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Flinders University</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators will study the effects of methotrexate on blood pressure, arterial&#xD;
      stiffness and endothelial function in patients with rheumatoid arthritis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with rheumatoid arthritis have an increased risk of stroke and heart attack when&#xD;
      compared to the rest of the population. Recent studies have shown that methotrexate, a&#xD;
      disease-modifying antirheumatic drug (DMARDs) commonly prescribed for rheumatoid arthritis,&#xD;
      reduces this risk. However, the mechanisms responsible for the protective effects of&#xD;
      methotrexate on the heart and the brain are unknown.&#xD;
&#xD;
      The investigators have recently completed an observational study in participants with&#xD;
      rheumatoid arthritis treated with either methotrexate or with other DMARDs. Participants on&#xD;
      methotrexate had lower blood pressure and 'healthier' blood vessels than participants treated&#xD;
      with other DMARDs. These differences were maintained over a period of 8 months. These results&#xD;
      suggest that methotrexate lowers blood pressure and exerts salutary effects on blood vessels,&#xD;
      which might explain the reduced risk of stroke and heart attack with this drug. However, the&#xD;
      observational nature of this study does not allow establishing a clear cause-effect&#xD;
      relationship between methotrexate treatment and the observed changes in blood pressure and&#xD;
      blood vessels.&#xD;
&#xD;
      In order to address this issue, the investigators will recruit participants that have been&#xD;
      recently diagnosed with rheumatoid arthritis and are about to start treatment with either&#xD;
      methotrexate (Group 1) or another DMARD (Group 2). Then, the investigators will assess their&#xD;
      blood pressure and blood vessels for 6 months. The investigators will use an injectable&#xD;
      (subcutaneous) form of methotrexate because this might provide better effects on blood&#xD;
      pressure and blood vessels. The investigators will also study a third group (Group 3) of&#xD;
      rheumatoid arthritis participants already on treatment (&gt; 1 year) with oral methotrexate,&#xD;
      with or without other DMARDs. They will be switched to subcutaneous methotrexate, but&#xD;
      continuing all their other medications, for 6 months to see whether the subcutaneous form can&#xD;
      further reduce blood pressure and provide additional salutary effects on blood vessels.&#xD;
      Finally, the investigators will study a fourth group (Group 4) of participants with&#xD;
      rheumatoid arthritis already on treatment (&gt; 1 year) with DMADRs other than methotrexate who&#xD;
      will continue with the same medications for 6 months, to assess possible fluctuations in&#xD;
      blood pressure and blood vessel markers over time.&#xD;
&#xD;
      Each participant will attend three study visits (baseline, 1 and 6 months), each lasting&#xD;
      between 60 and 90 min.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 4</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in peripheral systolic blood pressure</measure>
    <time_frame>Change from baseline peripheral systolic blood pressure at 6 months</time_frame>
    <description>Change in peripheral systolic blood pressure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in peripheral and central blood pressure</measure>
    <time_frame>Change from baseline peripheral and central blood pressure at 6 months</time_frame>
    <description>Change in peripheral and central blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in arterial stiffness</measure>
    <time_frame>Change from baseline pulse wave velocity at 6 months</time_frame>
    <description>Change in pulse wave velocity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in arterial wave reflection</measure>
    <time_frame>Change from baseline augmentation index at 6 months</time_frame>
    <description>Change in augmentation index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in adenosine</measure>
    <time_frame>Change from baseline adenosine concentrations at 6 months</time_frame>
    <description>Change in adenosine concentrations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in arginine metabolites</measure>
    <time_frame>Change from baseline ADMA concentrations at 6 months</time_frame>
    <description>Change in ADMA concentrations</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">124</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <condition>Stiffness, Aortic</condition>
  <condition>Endothelial Dysfunction</condition>
  <condition>Cardiovascular Risk Factor</condition>
  <arm_group>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Newly diagnosed RA patients started on subcutaneous MTX - open randomisation vs. sulfasalazine. In this group, use of NSAIDs, steroids, and/or other DMARDs, is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice .</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Newly diagnosed RA patients started on sulfasalazine - open randomisation vs. subcutaneous MTX. In this group, use of NSAIDs, steroids, and/or other DMARDs (except MTX), is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RA patients on long-term treatment (&gt; 1 year) with oral MTX, with or without other DMARDs, NSAIDs and/or steroids, switched to subcutaneous MTX (same dose). In these patients, treatment with other DMARDs, NSAIDs and/or steroids will continue. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 4</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>RA patients on stable treatment (&gt; 1 year) with other (non-MTX) DMARDs, with or without NSAIDs and/or steroids, and continued on the same treatment. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>See arm descriptions</description>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_label>Group 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sulfasalazine</intervention_name>
    <description>See arm description</description>
    <arm_group_label>Group 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Other DMARDs</intervention_name>
    <description>See arm</description>
    <arm_group_label>Group 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient with rheumatoid arthritis according to EULAR/ACR 2010 criteria.&#xD;
&#xD;
          -  Age ≥18 years.&#xD;
&#xD;
          -  Written informed consent, dated and signed before initiating any study-related&#xD;
             procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to MTX or sulfasalazine.&#xD;
&#xD;
          -  Patient who cannot be followed during 6 months.&#xD;
&#xD;
          -  Active alcohol or substance abuse within the last 12 months.&#xD;
&#xD;
          -  Participation in a clinical trial within 3 months prior to the start of the study.&#xD;
&#xD;
          -  Body mass index &gt;35 Kg/m2.&#xD;
&#xD;
          -  Secondary causes of hypertension.&#xD;
&#xD;
          -  Grade 2 (moderate) or 3 (severe) hypertension: clinic blood pressure &gt;160/100 mm Hg.&#xD;
&#xD;
          -  Resistant hypertension: clinical blood pressure ≥140/90 mm Hg despite concurrent use&#xD;
             of three antihypertensive agents of different classes, one of which is a diuretic.&#xD;
&#xD;
          -  Clinical systolic blood pressure &lt;100 mm Hg or history of symptomatic orthostatic&#xD;
             hypotension.&#xD;
&#xD;
          -  Cardiovascular event, procedure, or hospitalization for unstable angina with the last&#xD;
             6 months.&#xD;
&#xD;
          -  Atrial fibrillation.&#xD;
&#xD;
          -  Heart failure.&#xD;
&#xD;
          -  Treatment with nitrates.&#xD;
&#xD;
          -  Estimated glomerular filtration rate (eGFR) &lt;45 mL/min.&#xD;
&#xD;
          -  Diagnosis of polycystic kidney disease.&#xD;
&#xD;
          -  Glomerulonephritis treated with or likely to be treated with immunosuppressant drugs&#xD;
&#xD;
          -  Uncontrolled diabetes with HbA1c &gt;9.0% (&gt;75 mmol/mol).&#xD;
&#xD;
          -  Uncontrolled dyslipidaemia with total serum cholesterol &gt;7.5 mmol/L or triglycerides&#xD;
             &gt;5.6 mmol/L.&#xD;
&#xD;
          -  Clinical diagnosis of dementia, treatment with medications for dementia or, in the&#xD;
             opinion of the study staff, the participant is cognitively unable to follow the&#xD;
             protocol.&#xD;
&#xD;
          -  Other medical, psychiatric, or behavioural factors that in the judgment of the study&#xD;
             staff may interfere with study participation.&#xD;
&#xD;
          -  Cancer diagnosed and treated within the past 2 years that, in the judgment of the&#xD;
             study staff, would compromise a participant's ability to comply with the protocol and&#xD;
             complete the study.&#xD;
&#xD;
          -  Any organ transplant.&#xD;
&#xD;
          -  Pregnancy, currently trying to become pregnant, or of child bearing potential and not&#xD;
             using birth control.&#xD;
&#xD;
          -  Significant illness within 2 weeks of study start.&#xD;
&#xD;
          -  Patients with an unstable active medical condition that could impair evaluation of&#xD;
             study results.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Arduino A Mangoni, MD, PhD</last_name>
    <phone>0061882047495</phone>
    <email>arduino.mangoni@flinders.edu.au</email>
  </overall_contact>
  <location>
    <facility>
      <name>Southern Adelaide Local Health Network</name>
      <address>
        <city>Bedford Park</city>
        <state>South Australia</state>
        <zip>5042</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arduino Mangoni, MD, PhD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>August 16, 2017</study_first_submitted>
  <study_first_submitted_qc>August 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 18, 2017</study_first_posted>
  <last_update_submitted>July 25, 2022</last_update_submitted>
  <last_update_submitted_qc>July 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Flinders University</investigator_affiliation>
    <investigator_full_name>Arduino Mangoni</investigator_full_name>
    <investigator_title>Professor of Clinical Pharmacology</investigator_title>
  </responsible_party>
  <keyword>Methotrexate</keyword>
  <keyword>Rheumatoid arthritis</keyword>
  <keyword>Blood pressure</keyword>
  <keyword>Arterial stiffness</keyword>
  <keyword>Cardiovascular risk</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Arthritis</mesh_term>
    <mesh_term>Arthritis, Rheumatoid</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sulfasalazine</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 10, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/89/NCT03254589/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03254589
org study id: HREC/17/SAC/46
nct id: NCT03254589
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The investigators will study the effects of methotrexate on blood pressure, arterial
      stiffness and endothelial function in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis have an increased risk of stroke and heart attack when
      compared to the rest of the population. Recent studies have shown that methotrexate, a
      disease-modifying antirheumatic drug (DMARDs) commonly prescribed for rheumatoid arthritis,
      reduces this risk. However, the mechanisms responsible for the protective effects of
      methotrexate on the heart and the brain are unknown.

      The investigators have recently completed an observational study in participants with
      rheumatoid arthritis treated with either methotrexate or with other DMARDs. Participants on
      methotrexate had lower blood pressure and 'healthier' blood vessels than participants treated
      with other DMARDs. These differences were maintained over a period of 8 months. These results
      suggest that methotrexate lowers blood pressure and exerts salutary effects on blood vessels,
      which might explain the reduced risk of stroke and heart attack with this drug. However, the
      observational nature of this study does not allow establishing a clear cause-effect
      relationship between methotrexate treatment and the observed changes in blood pressure and
      blood vessels.

      In order to address this issue, the investigators will recruit participants that have been
      recently diagnosed with rheumatoid arthritis and are about to start treatment with either
      methotrexate (Group 1) or another DMARD (Group 2). Then, the investigators will assess their
      blood pressure and blood vessels for 6 months. The investigators will use an injectable
      (subcutaneous) form of methotrexate because this might provide better effects on blood
      pressure and blood vessels. The investigators will also study a third group (Group 3) of
      rheumatoid arthritis participants already on treatment (> 1 year) with oral methotrexate,
      with or without other DMARDs. They will be switched to subcutaneous methotrexate, but
      continuing all their other medications, for 6 months to see whether the subcutaneous form can
      further reduce blood pressure and provide additional salutary effects on blood vessels.
      Finally, the investigators will study a fourth group (Group 4) of participants with
      rheumatoid arthritis already on treatment (> 1 year) with DMADRs other than methotrexate who
      will continue with the same medications for 6 months, to assess possible fluctuations in
      blood pressure and blood vessel markers over time.

      Each participant will attend three study visits (baseline, 1 and 6 months), each lasting
      between 60 and 90 min.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Change in peripheral systolic blood pressure
time frame: Change from baseline peripheral systolic blood pressure at 6 months
description: Change in peripheral systolic blood pressure
measure: Change in peripheral and central blood pressure
time frame: Change from baseline peripheral and central blood pressure at 6 months
description: Change in peripheral and central blood pressure
measure: Change in arterial stiffness
time frame: Change from baseline pulse wave velocity at 6 months
description: Change in pulse wave velocity
measure: Change in arterial wave reflection
time frame: Change from baseline augmentation index at 6 months
description: Change in augmentation index
measure: Change in adenosine
time frame: Change from baseline adenosine concentrations at 6 months
description: Change in adenosine concentrations
measure: Change in arginine metabolites
time frame: Change from baseline ADMA concentrations at 6 months
description: Change in ADMA concentrations
arm group label: Group 1
arm group type: Experimental
description: Newly diagnosed RA patients started on subcutaneous MTX - open randomisation vs. sulfasalazine. In this group, use of NSAIDs, steroids, and/or other DMARDs, is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice .
arm group label: Group 2
arm group type: Active Comparator
description: Newly diagnosed RA patients started on sulfasalazine - open randomisation vs. subcutaneous MTX. In this group, use of NSAIDs, steroids, and/or other DMARDs (except MTX), is allowed, if indicated, for symptom control. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
arm group label: Group 3
arm group type: Experimental
description: RA patients on long-term treatment (> 1 year) with oral MTX, with or without other DMARDs, NSAIDs and/or steroids, switched to subcutaneous MTX (same dose). In these patients, treatment with other DMARDs, NSAIDs and/or steroids will continue. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
arm group label: Group 4
arm group type: Active Comparator
description: RA patients on stable treatment (> 1 year) with other (non-MTX) DMARDs, with or without NSAIDs and/or steroids, and continued on the same treatment. The overall management, tests and outpatient rheumatology visits schedule will be similar to other patients with RA, in accordance to standard practice.
intervention type: Drug
intervention name: Methotrexate
description: See arm descriptions
arm group label: Group 1
arm group label: Group 3
intervention type: Drug
intervention name: Sulfasalazine
description: See arm description
arm group label: Group 2
intervention type: Drug
intervention name: Other DMARDs
description: See arm
arm group label: Group 4
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Arduino A Mangoni, MD, PhD
phone: 0061882047495
email: arduino.mangoni@flinders.edu.au
facility: 
status: Recruiting
contact: 
country: Australia
responsible party type: Principal Investigator
investigator affiliation: Flinders University
investigator full name: Arduino Mangoni
investigator title: Professor of Clinical Pharmacology
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Sulfasalazine
mesh term: Methotrexate
provided document: 