<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/NCT01717859</url>
  </required_header>
  <id_info>
    <org_study_id>ML28542</org_study_id>
    <secondary_id>ML28542</secondary_id>
    <nct_id>NCT01717859</nct_id>
  </id_info>
  <brief_title>Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab</brief_title>
  <acronym>RASTS</acronym>
  <official_title>Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Los Angeles</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, Los Angeles</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to determine if a change in inflammation or baseline&#xD;
      inflammation seen on the ultrasound is a good indicator of how rheumatoid arthritis patients&#xD;
      respond to TCZ 4mg/kg and whether early prediction of dose escalation is possible by&#xD;
      utilizing ultrasound inflammatory measures.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a 24-week, double blind open label clinical trial study to evaluate 57 active&#xD;
      Rheumatoid Arthritis (RA) patients who have moderate to severe disease activity with total&#xD;
      Power Doppler Ultrasound (PDUS) &gt;10 of 34 joints evaluated by Ultrasound (US) (at screening&#xD;
      to enter into the study). All patients will begin treatment with tocilizumab at a dose of&#xD;
      4mg/kg. Two study sites will recruit patients (UCLA and UF) using the same protocol, after&#xD;
      standardizing US acquisition methods, as well as scoring. US synovitis scores will be&#xD;
      acquired at screening, baseline, and pre-infusion at 4, 12, 16, and 24 weeks, to be able to&#xD;
      determine whether change in pre-infusion synovitis score at 4 weeks can be used to predict&#xD;
      change in disease activity at 12 weeks. This will provide evidence to whether such reading is&#xD;
      useful in predicting which patients may require escalation of dose from 4 to 8 mg/kg. At 12&#xD;
      weeks, patients not meeting low disease activity within the 4mg/kg (disease activity score&#xD;
      DAS28/ Erythrocyte Sedimentation Rate (ESR)-4item&lt;3.2) will increase the tocilizumab dose to&#xD;
      8mg/kg (maximum dose 800mg) in a blinded manner to enable evaluation of these US-focused&#xD;
      objectives in the context of the current FDA-approved label. The ultrasound scorer will not&#xD;
      know information about patient's disease activity (Tender Joint Count (TJC), Swollen Joint&#xD;
      Count (SJC), labs etc) or if there was dose escalation at 12 weeks. The clinical assessor of&#xD;
      disease activity will be blinded to the ultrasound scores. Additionally, the patient will&#xD;
      also be blinded to dose escalation. If patients in the 4mg/kg arm achieve DAS28&lt;3.2 at 12&#xD;
      weeks, patients will continue with their current dose for the duration of the study. Please&#xD;
      see the below Table for details on the blinding plan.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">April 2017</completion_date>
  <primary_completion_date type="Actual">April 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</measure>
    <time_frame>Baseline, 3 Month</time_frame>
    <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</measure>
    <time_frame>Baseline, 6 Month</time_frame>
    <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</measure>
    <time_frame>Baseline, 3 Month</time_frame>
    <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</measure>
    <time_frame>Baseline, 6 Month</time_frame>
    <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 3 Change in DAS28/ESR</measure>
    <time_frame>Baseline, 3 month</time_frame>
    <description>28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 6 Change in DAS28/ESR</measure>
    <time_frame>Baseline, 6 Month</time_frame>
    <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 3 Change in CDAI</measure>
    <time_frame>Baseline, 3 month</time_frame>
    <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to Month 6 Change in CDAI</measure>
    <time_frame>Baseline, 6 Month</time_frame>
    <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">74</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>All subjects will receive tocilizumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
    <arm_group_label>Tocilizumab</arm_group_label>
    <other_name>Actemra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        Patients must have rheumatoid arthritis. Patients will be included in the trial based on&#xD;
        the following criteria:&#xD;
&#xD;
          1. Patient must meet 1987 American College of Rheumatology (ACR) criteria,&#xD;
&#xD;
          2. Age &gt; 18 years of age,&#xD;
&#xD;
          3. Baseline DAS28/ESR&gt;4.4,&#xD;
&#xD;
          4. Stable concomitant DMARDs for more than 1 month (methotrexate, leflunomide, plaquenil,&#xD;
             sulfasalazine, or no DMARDs). However, if the patient is not on DMARD, history of&#xD;
             DMARD use required.&#xD;
&#xD;
               1. If not on DMARD (and the patient satisfies the above statement), the patient can&#xD;
                  opt for monotherapy with tocilizumab or combination therapy OR&#xD;
&#xD;
               2. If on biologic monotherapy, can opt for monotherapy with tocilizumab or DMARD&#xD;
                  combination therapy (ie. patients cannot be on biologic with TCZ)&#xD;
&#xD;
        6) Power Doppler score of &gt;10 at screening.&#xD;
&#xD;
        General Medical Concerns:&#xD;
&#xD;
          -  Normal organ function, except if abnormal due to the disease under investigation&#xD;
&#xD;
          -  Men and women of reproductive potential must agree to use an acceptable method of&#xD;
             birth control during treatment and for six months after completion of treatment.&#xD;
&#xD;
          -  Subject has provided written informed consent.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        A patient will be excluded if the answer to any of the following statements is &quot;yes&quot;.&#xD;
&#xD;
        General:&#xD;
&#xD;
          1. Major surgery (including joint surgery) within 8 weeks prior to baseline or planned&#xD;
             major surgery within 6 months after baseline.&#xD;
&#xD;
             Excluded Previous or Concomitant Therapy:&#xD;
&#xD;
          2. Treatment with any investigational agent within 4 weeks (or 5 half-lives of the&#xD;
             investigational drug, whichever is longer) of baseline.&#xD;
&#xD;
          3. Previous treatment with any cell-depleting therapies, including investigational agents&#xD;
             or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3.&#xD;
&#xD;
          4. Previous treatment with anti-CD19 and anti-CD20 within 6 months of start of the study.&#xD;
&#xD;
          5. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6&#xD;
             months of baseline.&#xD;
&#xD;
          6. Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.&#xD;
&#xD;
          7. Previous treatment with TCZ.&#xD;
&#xD;
          8. Any previous treatment with alkylating agents such as chlorambucil, or with total&#xD;
             lymphoid irradiation.&#xD;
&#xD;
          9. Use of prednisone &gt; 10mg at baseline.&#xD;
&#xD;
             Exclusions for General Safety:&#xD;
&#xD;
         10. History of severe allergic or anaphylactic reactions to human, humanized or murine&#xD;
             monoclonal antibodies.&#xD;
&#xD;
         11. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary&#xD;
             (including obstructive pulmonary disease), renal, hepatic, endocrine (include&#xD;
             uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated&#xD;
             diverticulitis, ulcerative colitis, or Crohn's disease.)&#xD;
&#xD;
         12. Current liver disease as determined by principal investigator unless related to&#xD;
             primary disease under investigation&#xD;
&#xD;
         13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial&#xD;
             or other infections (including but not limited to tuberculosis and atypical&#xD;
             mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal&#xD;
             infections of nail beds).&#xD;
&#xD;
         14. Any major episode of infection requiring hospitalization or treatment with IV&#xD;
             antibiotics within 4 weeks of baseline or oral antibiotics within 2 weeks prior to&#xD;
             baseline.&#xD;
&#xD;
         15. Active Tuberculosis (TB) requiring treatment within the previous 3 years. Patients&#xD;
             should be screened for latent TB and, if positive, treated following local practice&#xD;
             guidelines prior to initiating TCZ. Patients treated for tuberculosis with no&#xD;
             recurrence in 3 years are permitted.&#xD;
&#xD;
         16. Primary or secondary immunodeficiency (history of or currently active) unless related&#xD;
             to primary disease under investigation.&#xD;
&#xD;
         17. Evidence of active malignant disease, malignancies diagnosed within the previous 5&#xD;
             years (including hematological malignancies and solid tumors, except basal and&#xD;
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has&#xD;
             been excised and cured), or breast cancer diagnosed within the previous 5 years.&#xD;
&#xD;
         18. Pregnant women or nursing (breast feeding) mothers.&#xD;
&#xD;
         19. Patients with reproductive potential not willing to use an effective method of&#xD;
             contraception.&#xD;
&#xD;
         20. History of alcohol, drug or chemical abuse within 1 year prior to screening.&#xD;
&#xD;
         21. Neuropathies or other conditions that might interfere with pain evaluation unless&#xD;
             related to primary disease under investigation.&#xD;
&#xD;
         22. Patients with lack of peripheral venous access.&#xD;
&#xD;
         23. Body weight of &gt; 150 kg.&#xD;
&#xD;
             Laboratory Exclusion criteria (at screening):&#xD;
&#xD;
         24. Serum creatinine &gt; 1.6 mg/dL (141 µmol/L) in female patients and &gt; 1.9 mg/dL (168&#xD;
             µmol/L) in male patients. Patients with serum creatinine values exceeding limits may&#xD;
             be eligible for the study if their estimated glomerular filtration rates (GFR) are&#xD;
             &gt;30.&#xD;
&#xD;
         25. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) &gt; 1.5 times upper&#xD;
             limit of normal (ULN)&#xD;
&#xD;
         26. Total Bilirubin &gt; ULN&#xD;
&#xD;
         27. Platelet count &lt; 100 x 109/L (100,000/mm3)&#xD;
&#xD;
         28. Hemoglobin &lt; 85 g/L (8.5 g/dL; 5.3 mmol/L)&#xD;
&#xD;
         29. White Blood Cells &lt; 3.0 x 109/L (3000/mm3)&#xD;
&#xD;
         30. Absolute Neutrophil Count &lt; 2.0 x 109/L (2000/mm3)&#xD;
&#xD;
         31. Absolute Lymphocyte Count &lt; 0.5 x 109/L (500/mm3)&#xD;
&#xD;
         32. Positive Hepatitis BsAg, or Hepatitis C antibody&#xD;
&#xD;
         33. HIV positive&#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_official>
    <last_name>Veena Ranganath, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>UCLA David Geffen School of Medicine, Division of Rheumatology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA David Geffen School of Medicine, Division of Rheumatology</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>October 19, 2012</study_first_submitted>
  <study_first_submitted_qc>October 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 31, 2012</study_first_posted>
  <results_first_submitted>July 9, 2018</results_first_submitted>
  <results_first_submitted_qc>October 30, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">November 29, 2018</results_first_posted>
  <last_update_submitted>May 6, 2019</last_update_submitted>
  <last_update_submitted_qc>May 6, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, Los Angeles</investigator_affiliation>
    <investigator_full_name>Dr. Veena Ranganath</investigator_full_name>
    <investigator_title>M.D., M.S., Assistant Clinical Professor</investigator_title>
  </responsible_party>
  <keyword>Rheumatoid Arthritis</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>
  <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>December 5, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/59/NCT01717859/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients were recruited through printed and internet advertisements, direct recruitment of study participants, referrals, review of medical records to identify potential participants, and through IRB approved screening protocol and IRB approved study. Patients were recruited starting on 9/24/14. The recruitment continued through November of 2016.</recruitment_details>
      <pre_assignment_details>16 did not pass inclusion criteria, these patients were not able to be assigned to a study arm: 8 had PDUS&lt;10 4 lab values outside limits&#xD;
pregnant&#xD;
changed their mind&#xD;
1 was taking prednisone.&#xD;
Also:&#xD;
4 other patients were assigned to the study arm but were deleted from the study due to the considerations mentioned in the protocol</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Tocilizumab</title>
          <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="54"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>3 Month</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Moved out of state</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Patient concerned about mental health</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Tocilizumab</title>
          <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="54"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51.87" spread="15.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Disease duration</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9.94" spread="7.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Disease Activity Score All Joints (DAS28)/ Erythrocyte Sedimentation Rate (ESR)</title>
          <description>DAS28 is a measure of disease activity in rheumatoid arthritis (RA). DAS stands for 'disease activity score' and the number 28 refers to the 28 joints that are examined in this assessment. The calculation takes into account the number of swollen joints, the number of tender joints (both out of 28 assessed joints), the erythrocyte sedimentation rate (ESR), and a self-reported global assessment of health from the patient. DAS28 ranges from 0 to a maximum of 9.48. A DAS28 more than 5.1 implies active disease, less than 3.2 implies low disease activity, and less than 2.6 implies remission.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.30" spread="1.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Clinical Disease Activity Index (CDAI)</title>
          <description>CDAI stands for &quot;Clinical Disease Activity Index&quot; and is a measure used to assess rheumatoid arthritis activity. This scale sums the count of swollen joints, the count of tender joints (both out of 28 assessed joints), and the final scores of both a patient global health assessment and a care provider global health assessment for the patient on a continuous scale from 0-10. CDAI ranges from 0 to 76, and &lt;2.8 implies remission, &lt;10.0 implies low disease activity, &lt;22.0 implies moderate disease activity, and &gt;22.0 implies high disease activity.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39.04" spread="11.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Health Assessment Questionnaire- Disability Index (HAQ-DI)</title>
          <description>HAQ-DI stands for Health Assessment Questionnaire- Disability Index. HAQ-DI is derived from the HAQ, Health Assessment Questionnaire, developed in the 1980's. The HAQ-DI measures the quality of life of the patient by asking the patient to report answers to their abilities to perform daily life tasks such as getting in and out of bed. It ranges from 0 to a maximum value of 3. Values in the range of 0 to 1 implies the patient has mild difficulties to moderate disability, 1 to 2 implies that the patient has a moderate to severe disability, and 2 to 3 implies a very severe disability.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.47" spread="0.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Max Joint Power Doppler Ultrasound (PDUS)</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint and the sum of these represents PDUS. The Power Doppler Synovitis Score (PDUS) ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. A higher value of the total score for PDUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="29.59" spread="16.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Max Joint Grey-Scale Ultrasound (GSUS)</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint and the sum of these represents GSUS. The grey scale synovial hypertrophy score (GSUS) ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. A higher value of the total score for GSUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.61" spread="14.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</title>
        <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
        <time_frame>Baseline, 3 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change of Total Power Doppler Synovitis Score 3 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.84" spread="13.09"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</title>
        <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
        <time_frame>Baseline, 6 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change of Total Power Doppler Synovitis Score 6 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores.&#xD;
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.16" spread="15.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</title>
        <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
        <time_frame>Baseline, 3 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change Total B-mode Synovial Hypertrophy Score 3 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.26" spread="12.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</title>
        <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
        <time_frame>Baseline, 6 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change Total B-mode Synovial Hypertrophy Score 6 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints</title>
          <description>34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores.&#xD;
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.00" spread="15.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 3 Change in DAS28/ESR</title>
        <description>28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
        <time_frame>Baseline, 3 month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change in DAS28/ESR 3 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 3 Change in DAS28/ESR</title>
          <description>28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.20" spread="1.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 6 Change in DAS28/ESR</title>
        <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
        <time_frame>Baseline, 6 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change in DAS28/ESR 6 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 6 Change in DAS28/ESR</title>
          <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores.&#xD;
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.32" spread="1.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 3 Change in CDAI</title>
        <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
        <time_frame>Baseline, 3 month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change in CDAI 3 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 3 Change in CDAI</title>
          <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.64" spread="10.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Baseline to Month 6 Change in CDAI</title>
        <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
        <time_frame>Baseline, 6 Month</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Mean Change in CDAI 6 Month</title>
            <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Baseline to Month 6 Change in CDAI</title>
          <description>28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores.&#xD;
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.70" spread="12.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Tocilizumab</title>
          <description>All subjects will receive tocilizumab.&#xD;
Tocilizumab: All subjects will start at 4mg/kg. After 3 months, if DAS28 &gt; 3.2, dosage will be escalated to 8 mg/kg.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast Cancer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="51" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dyslipidemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercholesterolemia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Loose Stool</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Falling Down</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Headaches</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Increased Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rheumatoid Arthritis Flare</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dry Cough</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Bruises on Different Body Sites</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Veena K. Ranganath</name_or_title>
      <organization>UCLA</organization>
      <phone>310-825-4321</phone>
      <email>vranganath@mednet.ucla.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01717859
org study id: ML28542
secondary id: ML28542
nct id: NCT01717859
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this research study is to determine if a change in inflammation or baseline
      inflammation seen on the ultrasound is a good indicator of how rheumatoid arthritis patients
      respond to TCZ 4mg/kg and whether early prediction of dose escalation is possible by
      utilizing ultrasound inflammatory measures.
This is a 24-week, double blind open label clinical trial study to evaluate 57 active
      Rheumatoid Arthritis (RA) patients who have moderate to severe disease activity with total
      Power Doppler Ultrasound (PDUS) >10 of 34 joints evaluated by Ultrasound (US) (at screening
      to enter into the study). All patients will begin treatment with tocilizumab at a dose of
      4mg/kg. Two study sites will recruit patients (UCLA and UF) using the same protocol, after
      standardizing US acquisition methods, as well as scoring. US synovitis scores will be
      acquired at screening, baseline, and pre-infusion at 4, 12, 16, and 24 weeks, to be able to
      determine whether change in pre-infusion synovitis score at 4 weeks can be used to predict
      change in disease activity at 12 weeks. This will provide evidence to whether such reading is
      useful in predicting which patients may require escalation of dose from 4 to 8 mg/kg. At 12
      weeks, patients not meeting low disease activity within the 4mg/kg (disease activity score
      DAS28/ Erythrocyte Sedimentation Rate (ESR)-4item<3.2) will increase the tocilizumab dose to
      8mg/kg (maximum dose 800mg) in a blinded manner to enable evaluation of these US-focused
      objectives in the context of the current FDA-approved label. The ultrasound scorer will not
      know information about patient's disease activity (Tender Joint Count (TJC), Swollen Joint
      Count (SJC), labs etc) or if there was dose escalation at 12 weeks. The clinical assessor of
      disease activity will be blinded to the ultrasound scores. Additionally, the patient will
      also be blinded to dose escalation. If patients in the 4mg/kg arm achieve DAS28<3.2 at 12
      weeks, patients will continue with their current dose for the duration of the study. Please
      see the below Table for details on the blinding plan.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Baseline to Month 3 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)
time frame: Baseline, 3 Month
description: 34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Power Doppler scores.
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.
measure: Baseline to Month 6 Change in Total Power Doppler Synovitis Score of 34 Joints (Range 0 - 102)
time frame: Baseline, 6 Month
description: 34 joints will be evaluated using a 0 to 3 point scale for each joint. Power Doppler synovitis score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Power Doppler scores.
This scale is called the Power Doppler Synovitis Score (PDUS). It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for PDUS represents more severe disease level.
measure: Baseline to Month 3 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints
time frame: Baseline, 3 Month
description: 34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 3 Month Synovial Hypertrophy Scores.
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.
measure: Baseline to Month 6 Change in Total B-mode Synovial Hypertrophy Score of 34 Joints
time frame: Baseline, 6 Month
description: 34 joints will be evaluated using a 0 to 3 point scale for each joint. Synovial hypertrophy score is the sum of all the joint scores. Change scores are calculated by subtracting Baseline minus 6 Month Synovial Hypertrophy Scores.
This scale is called the Grey Scale Synovial Hypertrophy Score (GSUS). Please note that B-mode is the same as GSUS. It ranges from 0 to 102. Scores of 0 indicate the least amount of inflammation of the joint while scores of 3 indicate the most amount of inflammation. Therefore, a higher value of the total score for GSUS represents more severe disease level.
measure: Baseline to Month 3 Change in DAS28/ESR
time frame: Baseline, 3 month
description: 28 joints will be evaluated for Tender Joint Count (TJC) and Swollen Joint Count (SJC) as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 3 Month Disease Activity Score (DAS) scores.
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.
measure: Baseline to Month 6 Change in DAS28/ESR
time frame: Baseline, 6 Month
description: 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit, finally the ESR lab value will be included in the total calculation. Change scores are calculated by subtracting Baseline minus 6 Month DAS scores.
The scale being used is called the Disease Activity Score for 28 Joints (DAS28) using the Erythrocyte Sedimentation Rate (ESR) in the calculation rather than the C Reactive Protein (CRP). The scale ranges from 0 to 9.4. Values of DAS28 below 2.6 imply remission, below 3.2 imply low disease activity and greater than 5.1 implies active disease.
measure: Baseline to Month 3 Change in CDAI
time frame: Baseline, 3 month
description: 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 3 Month CDAI scores.
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.
measure: Baseline to Month 6 Change in CDAI
time frame: Baseline, 6 Month
description: 28 joints will be evaluated for TJC and SJC as well as patient and physician global values assessed at the time of each visit. Change scores are calculated by subtracting Baseline minus 6 Month CDAI scores.
The scale being used is called the Clinical Disease Activity Index (CDAI) and has a range of 0 to 76. Values of CDAI below 2.8 imply remission, below 10 imply low disease activity, below 22 imply moderate disease activity, and above 22 implies high disease activity.
arm group label: Tocilizumab
arm group type: Other
description: All subjects will receive tocilizumab.
intervention type: Drug
intervention name: Tocilizumab
description: All subjects will start at 4mg/kg. After 3 months, if DAS28 > 3.2, dosage will be escalated to 8 mg/kg.
arm group label: Tocilizumab
other name: Actemra
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Veena Ranganath, MD, MS
role: Principal Investigator
affiliation: UCLA David Geffen School of Medicine, Division of Rheumatology
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, Los Angeles
investigator full name: Dr. Veena Ranganath
investigator title: M.D., M.S., Assistant Clinical Professor
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 