<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/NCT01661140</url>
  </required_header>
  <id_info>
    <org_study_id>ML28096</org_study_id>
    <secondary_id>2011-005260-20</secondary_id>
    <nct_id>NCT01661140</nct_id>
  </id_info>
  <brief_title>A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate in Patients With Severe Active Rheumatoid Arthritis, Comparing Tapering Versus Maintaining the Methotrexate Dosage</brief_title>
  <official_title>Randomized, Phase IV, Placebo-controlled, Comparative Study to Evaluate the Efficacy and Safety of Tapering Methotrexate (MTX) Dosage Versus Maintaining the Dosage in Patients With Severe Active Rheumatoid Arthritis (RA) Who Have Demonstrated an Inadequate Response (IR) to Prior Disease-modifying Anti-rheumatic Drugs (DMARDs) Treatment and Have Initiated RoActemra (RoActemra, TCZ) in Combination With MTX</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hoffmann-La Roche</source>
  <brief_summary>
    <textblock>
      This randomized, placebo-controlled, double-blind study will compare the safety and efficacy&#xD;
      of tapering methotrexate (MTX) versus maintaining MTX dosage in patients with severe active&#xD;
      rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs&#xD;
      (DMARDs) initiated on treatment with tocilizumab. Participants will receive tocilizumab 8&#xD;
      mg/kg intravenously every 4 weeks and MTX orally weekly throughout the study. At Week 24,&#xD;
      participants achieving a good/moderate EULAR response will be randomized receiving the MTX&#xD;
      Tapering arm or MTX Maintenance arm. Up to Week 56 participants will receive either tapering&#xD;
      or stable dose MTX in combination with tocilizumab. From Week 56 to Week 72 participants will&#xD;
      receive tocilizumab monotherapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">February 2015</completion_date>
  <primary_completion_date type="Actual">February 2015</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60</measure>
    <time_frame>From randomization to Week 60</time_frame>
    <description>Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (&lt;=) 3.2 and reduction of greater than (&gt;) 1.2 points were assessed as having a 'good' response. Participants with a score &gt;3.2 with reduction of &gt;1.2 points, or a score &lt;=5.1 with reduction of &gt;0.6 to &lt;=1.2 points, were assessed as having a 'moderate' response. Participants with a score &gt;5.1 with reduction of &gt;0.6 to &lt;=1.2 points, or any score with reduction &lt;=0.6 points, were assessed as non-responders with response recorded as 'none.'</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60</measure>
    <time_frame>Randomization (Week 24), Week 60</time_frame>
    <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72</measure>
    <time_frame>Randomization (Week 24), Week 72</time_frame>
    <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve Score of &lt;=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72</measure>
    <time_frame>Week 60, 72</time_frame>
    <description>Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) &lt;= 3.2</measure>
    <time_frame>Week 60, 72</time_frame>
    <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve score &lt;=3.2 at weeks 60 and 72 were reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve DAS28 Remission (DAS28 &lt; 2.6)</measure>
    <time_frame>Week 60, 72</time_frame>
    <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score &lt;2.6 at weeks 60 and 72 were reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) &gt;=1.2</measure>
    <time_frame>Week 60, 72</time_frame>
    <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 &gt;=1.2 score at weeks 60 and 72 were reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI &lt; 2.8) at Week 60 and 72</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI &lt; 3.3) at Week 60 and 72</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Anemia</measure>
    <time_frame>Week 0 up to Week 72</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)</measure>
    <time_frame>Week 0 up to Week 72</time_frame>
    <description>An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Able to Discontinue Methotrexate</measure>
    <time_frame>Week 0 up to Week 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP</measure>
    <time_frame>Randomization (Week 24), Week 60, Week 72</time_frame>
    <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP</measure>
    <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
    <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">427</enrollment>
  <condition>Rheumatoid Arthritis</condition>
  <arm_group>
    <arm_group_label>Methotrexate (MTX) Tapering Dosage</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will receive a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Methotrexate (MTX) Maintenance Dosage</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will continue to be administered a stable dose of MTX in a double-blind fashion between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate (stable dose)</intervention_name>
    <description>Methotrexate (MTX) was administered weekly according to the subject's pre-study MTX dose</description>
    <arm_group_label>Methotrexate (MTX) Maintenance Dosage</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>8 mg/kg intravenously every 4 weeks for 72 weeks</description>
    <arm_group_label>Methotrexate (MTX) Maintenance Dosage</arm_group_label>
    <arm_group_label>Methotrexate (MTX) Tapering Dosage</arm_group_label>
    <other_name>RoActemra/Actemra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate (tapering dose)</intervention_name>
    <description>Tapering doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. Tapering doses depended on dose administered to the subject during the open label period. First tapering occurred at randomization (Week 24), second tapering at Week 32, third tapering at Week 40 and final tapering at Week 48.</description>
    <arm_group_label>Methotrexate (MTX) Tapering Dosage</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients, &gt;/= 18 years of age&#xD;
&#xD;
          -  Active severe rheumatoid arthritis (DAS28 &gt; 5.1) according to European League of&#xD;
             Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria&#xD;
&#xD;
          -  Inadequate response to a trial of 2 DMARDs, including methotrexate, a trial being&#xD;
             defined as 6 months with 2 months at standard dose; no previous treatment with a&#xD;
             biologic agent such as a tumor necrosis factor (TNF) inhibitor&#xD;
&#xD;
          -  Oral corticosteroids must have been at a stable dose of &lt;/= 10 mg/day prednisolone or&#xD;
             equivalent for at least 25 out of 28 days prior to start of treatment (Day 1)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major surgery (including joint surgery) within 8 weeks prior to screening or planned&#xD;
             major surgery within 6 months following randomization&#xD;
&#xD;
          -  Rheumatic autoimmune disease other than rheumatoid arthritis&#xD;
&#xD;
          -  Functional class IV as defined by the ACR Classification of Functional Status in RA&#xD;
&#xD;
          -  Prior history of or current inflammatory joint disease other than RA&#xD;
&#xD;
          -  Previous treatment with tocilizumab&#xD;
&#xD;
          -  Previous treatment with any biologic drug (e.g. TNF inhibitor) that is used in the&#xD;
             treatment of RA&#xD;
&#xD;
          -  Intraarticular or parenteral corticosteroids within 6 weeks prior to enrollment&#xD;
&#xD;
          -  Inadequate liver, bone marrow or hepatic function&#xD;
&#xD;
          -  Positive for hepatitis B, hepatitis C or HIV infection&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Females of child-bearing potential who are not using reliable means of contraception&#xD;
&#xD;
          -  History of severe allergic or anaphylactic reactions to human, humanized or murine&#xD;
             monoclonal antibodies&#xD;
&#xD;
          -  Active current or history of recurrent bacterial, viral, fungal, mycobacterial or&#xD;
             other infections&#xD;
&#xD;
          -  History of, or currently active, primary or secondary immunodeficiency&#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>Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>Hoffmann-La Roche</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Aberdeen</city>
        <zip>AB25 2ZN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Abergavenny</city>
        <zip>NP7 7EG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ashford</city>
        <zip>TW15 3AA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Aylesbury</city>
        <zip>HP21 8AL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barnsley</city>
        <zip>S75 2EP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Basingstoke</city>
        <zip>RG24 9NA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bournemouth</city>
        <zip>BH23 2JX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Brighton</city>
        <zip>BN2 5BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bury St Edmonds</city>
        <zip>IP33 2QZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cambridge</city>
        <zip>CB2 2QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cannock</city>
        <zip>WS11 5XY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chelmsford</city>
        <zip>CM1 7ET</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chester</city>
        <zip>CH2 1UL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Coventry</city>
        <zip>CV2 2DX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Crewe</city>
        <zip>CW1 4QJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Darlington</city>
        <zip>DL3 6HX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Derby</city>
        <zip>DE22 3NE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dudley</city>
        <zip>DY1 2HQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dundee</city>
        <zip>DD12 9SY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Eastbourne</city>
        <zip>BN21 2UD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Exeter</city>
        <zip>EX2 5DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Gillingham</city>
        <zip>ME7 5NY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Greenock</city>
        <zip>PA16 0XN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Guildford</city>
        <zip>GU2 7XX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Harrogate</city>
        <zip>HG2 7SX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hull</city>
        <zip>HU3 3JZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Isle of Wight</city>
        <zip>PO30 5TG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Leeds</city>
        <zip>LS7 4SA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Liverpool</city>
        <zip>L9 7AL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Llantrisant</city>
        <zip>CF72 8XR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Londonderry</city>
        <zip>BT47 6SB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <zip>E11 1NR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <zip>SE18 4QH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <zip>SW17 0QT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>London</city>
        <zip>W6 8RF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Maidstone</city>
        <zip>ME16 9QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Manchester</city>
        <zip>M13 9PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Manchester</city>
        <zip>M41 5SL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Middlesborough</city>
        <zip>TS4 3BW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>North Shields</city>
        <zip>NE29 8NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Northampton</city>
        <zip>NN1 5BD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nottingham</city>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oldham</city>
        <zip>OL1 1NL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Plymouth</city>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Reading</city>
        <zip>RG1 5AN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Salford</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Salisbury</city>
        <zip>SP2 8BJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sheffield</city>
        <zip>S10 2JF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Somerset</city>
        <zip>TA1 5DA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Southport</city>
        <zip>PR8 6PN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Stevenage</city>
        <zip>SG1 4AB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Stoke-on-trent</city>
        <zip>ST6 7AG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sunderland</city>
        <zip>SR4 7TP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sutton in Ashfield</city>
        <zip>NG17 4JL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Swindon</city>
        <zip>SN3 6BB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Torquay</city>
        <zip>TQ2 7AA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Truro</city>
        <zip>TR1 3LJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Walsall</city>
        <zip>WS2 9PS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Warwick</city>
        <zip>CV34 5BW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Westcliffe-on-sea</city>
        <zip>SS0 0RY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wirral</city>
        <zip>CH49 5PE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wolverhampton</city>
        <zip>WV10 0QP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Worthing</city>
        <zip>BN11 2DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Wrightington</city>
        <zip>WN6 9EP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>York</city>
        <zip>YO31 8HE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <results_first_submitted>April 26, 2016</results_first_submitted>
  <results_first_submitted_qc>August 19, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">October 14, 2016</results_first_posted>
  <last_update_submitted>August 19, 2016</last_update_submitted>
  <last_update_submitted_qc>August 19, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 14, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>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>Methotrexate</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>The initial open label period of the study consisted of one group of 427 participants. After completion of the initial phase only participants, who achieved a good/moderate disease response, were randomized into the double blind period. 272 participants were randomized into the two arms entering the double-blind period of the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Initial Phase</title>
          <description>At Week 0 participants started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.</description>
        </group>
        <group group_id="P2">
          <title>Methotrexate (MTX) Tapering Group</title>
          <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
        </group>
        <group group_id="P3">
          <title>Methotrexate (MTX) Maintenance Group</title>
          <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Open-Label Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="427">All participants entered the study in the initial phase for 24 weeks of open label treatment.</participants>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="351"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="76"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Investigator Decision</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Administrative/Other</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor termination</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Did not meet EULAR criteria</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Double-Blind Period</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0">Those with a good/moderate disease response in the initial phase were randomized to the MTX arms.</participants>
                <participants group_id="P2" count="136">Only those with a good/moderate disease response in the initial phase were randomized.</participants>
                <participants group_id="P3" count="136">Only those with a good/moderate disease response in the initial phase were randomized.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="95"/>
                <participants group_id="P3" count="86"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="41"/>
                <participants group_id="P3" count="50"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Refused Treatment</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="16"/>
                <participants group_id="P3" count="18"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Investigator's Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Termination</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Administrative/Other</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Initial Phase</title>
          <description>At Week 0 participants started open-label tocilizumab and open-label MTX for 24 weeks.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="427"/>
          </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="55.0" spread="12.03"/>
                  </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="326"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="101"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60</title>
        <description>Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (&lt;=) 3.2 and reduction of greater than (&gt;) 1.2 points were assessed as having a 'good' response. Participants with a score &gt;3.2 with reduction of &gt;1.2 points, or a score &lt;=5.1 with reduction of &gt;0.6 to &lt;=1.2 points, were assessed as having a 'moderate' response. Participants with a score &gt;5.1 with reduction of &gt;0.6 to &lt;=1.2 points, or any score with reduction &lt;=0.6 points, were assessed as non-responders with response recorded as 'none.'</description>
        <time_frame>From randomization to Week 60</time_frame>
        <population>Intention to treat (ITT) population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60</title>
          <description>Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (&lt;=) 3.2 and reduction of greater than (&gt;) 1.2 points were assessed as having a 'good' response. Participants with a score &gt;3.2 with reduction of &gt;1.2 points, or a score &lt;=5.1 with reduction of &gt;0.6 to &lt;=1.2 points, were assessed as having a 'moderate' response. Participants with a score &gt;5.1 with reduction of &gt;0.6 to &lt;=1.2 points, or any score with reduction &lt;=0.6 points, were assessed as non-responders with response recorded as 'none.'</description>
          <population>Intention to treat (ITT) population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76.5"/>
                    <measurement group_id="O2" value="65.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Comparison was Tapering MTX : MTX maintenance. Last post-baseline EULAR response recorded used for participants with a missing result at Week 60.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Non-inferiority if the difference between treatments is statistically significant and the lower limit of the 95% confidence interval (CI) is greater than 0.9.</non_inferiority_desc>
            <p_value>0.036</p_value>
            <method>Analysis by logistic regression</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.803</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.037</ci_lower_limit>
            <ci_upper_limit>3.133</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60</title>
        <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
        <time_frame>Randomization (Week 24), Week 60</time_frame>
        <population>ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this end point.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60</title>
          <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
          <population>ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this end point.</population>
          <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="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (n= 135, 136)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.572" spread="1.3218"/>
                    <measurement group_id="O2" value="2.573" spread="1.3017"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 60 (n= 134, 135)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.179" spread="1.1702"/>
                    <measurement group_id="O2" value="-0.233" spread="1.5156"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72</title>
        <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
        <time_frame>Randomization (Week 24), Week 72</time_frame>
        <population>ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72</title>
          <description>The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.</description>
          <population>ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.</population>
          <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="134"/>
                <count group_id="O2" value="135"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.105" spread="1.2262"/>
                    <measurement group_id="O2" value="-0.224" spread="1.4961"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve Score of &lt;=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72</title>
        <description>Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.</description>
        <time_frame>Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy..</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve Score of &lt;=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72</title>
          <description>Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TJC &lt;=1, Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39.0"/>
                    <measurement group_id="O2" value="39.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SJC &lt;=1, Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.1"/>
                    <measurement group_id="O2" value="58.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TJC &lt;=1, Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.5"/>
                    <measurement group_id="O2" value="40.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SJC &lt;=1, Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.9"/>
                    <measurement group_id="O2" value="60.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) &lt;= 3.2</title>
        <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve score &lt;=3.2 at weeks 60 and 72 were reported.</description>
        <time_frame>Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) &lt;= 3.2</title>
          <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve score &lt;=3.2 at weeks 60 and 72 were reported.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.6"/>
                    <measurement group_id="O2" value="62.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="61.0"/>
                    <measurement group_id="O2" value="60.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve DAS28 Remission (DAS28 &lt; 2.6)</title>
        <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score &lt;2.6 at weeks 60 and 72 were reported.</description>
        <time_frame>Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve DAS28 Remission (DAS28 &lt; 2.6)</title>
          <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score &lt;2.6 at weeks 60 and 72 were reported.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.5"/>
                    <measurement group_id="O2" value="47.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.0"/>
                    <measurement group_id="O2" value="51.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) &gt;=1.2</title>
        <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 &gt;=1.2 score at weeks 60 and 72 were reported.</description>
        <time_frame>Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) &gt;=1.2</title>
          <description>The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 &gt;=1.2 score at weeks 60 and 72 were reported.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.6"/>
                    <measurement group_id="O2" value="16.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.6"/>
                    <measurement group_id="O2" value="15.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI &lt; 2.8) at Week 60 and 72</title>
        <description>Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI &lt; 2.8) at Week 60 and 72</title>
          <description>Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9"/>
                    <measurement group_id="O2" value="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5"/>
                    <measurement group_id="O2" value="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI &lt; 3.3) at Week 60 and 72</title>
        <description>Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI &lt; 3.3) at Week 60 and 72</title>
          <description>Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9"/>
                    <measurement group_id="O2" value="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9"/>
                    <measurement group_id="O2" value="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72</title>
        <description>The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72</title>
          <description>The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Improvement at Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.0"/>
                    <measurement group_id="O2" value="39.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Improvement at Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.5"/>
                    <measurement group_id="O2" value="50.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72</title>
        <description>The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72</title>
          <description>The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Improvement at Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.0"/>
                    <measurement group_id="O2" value="50.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Improvement at Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.2"/>
                    <measurement group_id="O2" value="56.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72</title>
        <description>Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72</title>
          <description>Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.</description>
          <population>ITT population included all randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Improvement at Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.2"/>
                    <measurement group_id="O2" value="10.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Improvement at Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.8"/>
                    <measurement group_id="O2" value="15.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Anemia</title>
        <time_frame>Week 0 up to Week 72</time_frame>
        <population>Safety population included all the randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Anemia</title>
          <population>Safety population included all the randomized participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5"/>
                    <measurement group_id="O2" value="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)</title>
        <description>An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.</description>
        <time_frame>Week 0 up to Week 72</time_frame>
        <population>Safety population included all the randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)</title>
          <description>An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.</description>
          <population>Safety population included all the randomized participants.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98"/>
                    <measurement group_id="O2" value="98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Able to Discontinue Methotrexate</title>
        <time_frame>Week 0 up to Week 60</time_frame>
        <population>Data were not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Able to Discontinue Methotrexate</title>
          <population>Data were not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)</title>
        <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>ITT population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)</title>
          <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities.</description>
          <population>ITT population included all randomized participants.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 60</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 72</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                    <measurement group_id="O2" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP</title>
        <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.</description>
        <time_frame>Randomization (Week 24), Week 60, Week 72</time_frame>
        <population>Participants in the ITT population with available data were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP</title>
          <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.</description>
          <population>Participants in the ITT population with available data were analyzed.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Hours actually worked (HAW), Week 60 (n=33, 17)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.0" lower_limit="0" upper_limit="58"/>
                    <measurement group_id="O2" value="28.0" lower_limit="0" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 in HAW, Week 60 (n=29, 17)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.0" lower_limit="-47" upper_limit="40"/>
                    <measurement group_id="O2" value="2.0" lower_limit="-43" upper_limit="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Work hours missed (WHM) to RA, Week 60 (n=33, 17)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="0" upper_limit="15"/>
                    <measurement group_id="O2" value="0.0" lower_limit="0" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 in WHM RA, Week 60 (n=30, 16)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-30" upper_limit="15"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-7" upper_limit="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>WHM other, Week 60 (n=33, 17)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="0" upper_limit="46"/>
                    <measurement group_id="O2" value="0.0" lower_limit="0" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 WHM other, Week 60 (n=30, 16)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-56" upper_limit="46"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-38" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>HAW, Week 72 (n=23, 13)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.0" lower_limit="0" upper_limit="48"/>
                    <measurement group_id="O2" value="16.0" lower_limit="0" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 in HAW, Week 72, (n=20, 12)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-37" upper_limit="23"/>
                    <measurement group_id="O2" value="2.5" lower_limit="-30" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>WHM to RA, Week 72 (n=23, 13)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="0" upper_limit="37"/>
                    <measurement group_id="O2" value="0.0" lower_limit="0" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 in WHM RA, Week 72 (n=21, 11)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-30" upper_limit="37"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-7" upper_limit="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>WHM other, Week 72 (n=23, 13)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="0" upper_limit="30"/>
                    <measurement group_id="O2" value="0.0" lower_limit="0" upper_limit="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Week 24 WHM other, Week 72 (n=21, 11)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-56" upper_limit="30"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-38" upper_limit="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP</title>
        <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.</description>
        <time_frame>Randomization (Week 24), Week 60, 72</time_frame>
        <population>Participants in the ITT population with available data at the respective time points were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Methotrexate (MTX) Tapering Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
          <group group_id="O2">
            <title>Methotrexate (MTX) Maintenance Group</title>
            <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP</title>
          <description>The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.</description>
          <population>Participants in the ITT population with available data at the respective time points were analyzed.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="136"/>
                <count group_id="O2" value="136"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Productivity (P), Week 60 (n=34, 18)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.0" lower_limit="0" upper_limit="8"/>
                    <measurement group_id="O2" value="2.0" lower_limit="0" upper_limit="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in P from Week 24 at Week 60 (n=30, 16)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" lower_limit="-6" upper_limit="8"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-5" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Regular Daily Activities (RDA), Week 60 (n=60, 45)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" lower_limit="0" upper_limit="9"/>
                    <measurement group_id="O2" value="3.0" lower_limit="0" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in RDA from Week 24 at Week 60 (n=59, 44)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-5" upper_limit="7"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-6" upper_limit="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Productivity (P), Week 72 (n=24, 12)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" lower_limit="0" upper_limit="8"/>
                    <measurement group_id="O2" value="3.0" lower_limit="0" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in P from Week 24 at Week 72 (n=21, 11)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-3" upper_limit="4"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-5" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Regular Daily Activities (RDA), Week 72 (n=42, 31)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" lower_limit="0" upper_limit="10"/>
                    <measurement group_id="O2" value="3.0" lower_limit="0" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in RDA from Week 24 at Week 72 (n=41, 29)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-5" upper_limit="4"/>
                    <measurement group_id="O2" value="-1.0" lower_limit="-5" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From start of treatment to unscheduled visit (up to Week 72)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Initial Phase</title>
          <description>At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks, which is the initial phase of the study.&#xD;
Adverse events in this reporting group are those occurring in the open-label phase only.</description>
        </group>
        <group group_id="E2">
          <title>Methotrexate (MTX) Tapering Group</title>
          <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.&#xD;
Adverse events in this reporting group are those occurring in the double-blind phase only.</description>
        </group>
        <group group_id="E3">
          <title>Methotrexate (MTX) Maintenance Group</title>
          <description>After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.&#xD;
Adverse events in this reporting group are those occurring in the double-blind phase only.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (18.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Enterovesical Fistula</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Rectal Haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Device Dislocation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Abdominal Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Bursitis Infective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Lymph Node Tuberculosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Necrotising Fasciitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Arthritis Infective</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Clostridium Difficile Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Lower Respiratory Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pneumocystis Jirovecii Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Tooth Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Viral Labyrinthitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Ankle Fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Joint Dislocation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Multiple Fractures</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood Bilirubin Increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Costochondritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pain In Extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Colon Neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Carcinoid Tumour Of The Gastrointestinal Tract</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Carotid Artery Dissection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Interstitial Lung Disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pleurisy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Pulmonary Fibrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Telangiectasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (18.0)</default_vocab>
        <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="263" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="62" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="70" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="54" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Mouth Ulceration</sub_title>
                <counts group_id="E1" subjects_affected="48" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="61" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Lower Respiratory Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="51" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Musculoskeletal Pain</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal Pain</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="136"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="136"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="32" subjects_at_risk="427"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="136"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="136"/>
              </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>The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Medical Communications</name_or_title>
      <organization>Hoffmann-La Roche</organization>
      <phone>800 821-8590</phone>
      <email>genentech@druginfo.com</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/NCT01661140
org study id: ML28096
secondary id: 2011-005260-20
nct id: NCT01661140
lead sponsor: 
This randomized, placebo-controlled, double-blind study will compare the safety and efficacy
      of tapering methotrexate (MTX) versus maintaining MTX dosage in patients with severe active
      rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs
      (DMARDs) initiated on treatment with tocilizumab. Participants will receive tocilizumab 8
      mg/kg intravenously every 4 weeks and MTX orally weekly throughout the study. At Week 24,
      participants achieving a good/moderate EULAR response will be randomized receiving the MTX
      Tapering arm or MTX Maintenance arm. Up to Week 56 participants will receive either tapering
      or stable dose MTX in combination with tocilizumab. From Week 56 to Week 72 participants will
      receive tocilizumab monotherapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60
time frame: From randomization to Week 60
description: Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (<=) 3.2 and reduction of greater than (>) 1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score <=5.1 with reduction of >0.6 to <=1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to <=1.2 points, or any score with reduction <=0.6 points, were assessed as non-responders with response recorded as 'none.'
measure: Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60
time frame: Randomization (Week 24), Week 60
description: The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
measure: Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72
time frame: Randomization (Week 24), Week 72
description: The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.
measure: Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72
time frame: Week 60, 72
description: Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.
measure: Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2
time frame: Week 60, 72
description: The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve score <=3.2 at weeks 60 and 72 were reported.
measure: Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6)
time frame: Week 60, 72
description: The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve DAS28 remission score <2.6 at weeks 60 and 72 were reported.
measure: Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2
time frame: Week 60, 72
description: The DAS28 index was calculated using the following formula: The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x patient global assessment of disease activity]. Participants who achieve cDAS28 >=1.2 score at weeks 60 and 72 were reported.
measure: Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72
time frame: Randomization (Week 24), Week 60, 72
description: Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.
measure: Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72
time frame: Randomization (Week 24), Week 60, 72
description: Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.
measure: Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72
time frame: Randomization (Week 24), Week 60, 72
description: The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.
measure: Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72
time frame: Randomization (Week 24), Week 60, 72
description: The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.
measure: Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72
time frame: Randomization (Week 24), Week 60, 72
description: Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.
measure: Percentage of Participants With Anemia
time frame: Week 0 up to Week 72
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
time frame: Week 0 up to Week 72
description: An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.
measure: Percentage of Participants Able to Discontinue Methotrexate
time frame: Week 0 up to Week 60
measure: Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP)
time frame: Randomization (Week 24), Week 60, 72
description: The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities.
measure: Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP
time frame: Randomization (Week 24), Week 60, Week 72
description: The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.
measure: Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP
time frame: Randomization (Week 24), Week 60, 72
description: The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.
arm group label: Methotrexate (MTX) Tapering Dosage
arm group type: Experimental
description: At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will receive a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.
arm group label: Methotrexate (MTX) Maintenance Dosage
arm group type: Active Comparator
description: At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks. At Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response will be randomized to the MTX Tapering group or MTX Maintenance group. In this arm participants will continue to be administered a stable dose of MTX in a double-blind fashion between Week 24 and Week 56. Participants will also continue to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants will receive tocilizumab monotherapy.
intervention type: Drug
intervention name: Methotrexate (stable dose)
description: Methotrexate (MTX) was administered weekly according to the subject's pre-study MTX dose
arm group label: Methotrexate (MTX) Maintenance Dosage
intervention type: Drug
intervention name: Tocilizumab
description: 8 mg/kg intravenously every 4 weeks for 72 weeks
arm group label: Methotrexate (MTX) Maintenance Dosage
arm group label: Methotrexate (MTX) Tapering Dosage
other name: RoActemra/Actemra
intervention type: Drug
intervention name: Methotrexate (tapering dose)
description: Tapering doses of methotrexate (MTX) were administered weekly from Week 24 to Week 56. Tapering doses depended on dose administered to the subject during the open label period. First tapering occurred at randomization (Week 24), second tapering at Week 32, third tapering at Week 40 and final tapering at Week 48.
arm group label: Methotrexate (MTX) Tapering Dosage
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Trials
role: Study Director
affiliation: Hoffmann-La Roche
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country: United Kingdom
responsible party type: Sponsor
mesh term: Arthritis
mesh term: Arthritis, Rheumatoid
mesh term: Methotrexate
participant flow: 
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outcome list: 
reported events: 
certain agreements: 
point of contact: 