Back to resultsA Study of Tocilizumab and Methotrexate Treatment Strategies (Adding Tocilizumab to Methotrexate Versus Switching to Tocilizumab) in Patients With Active Rheumatoid Arthritis With Inadequate Response to Prior Methotrexate Treatment
Primary Purpose
Rheumatoid Arthritis
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
tocilizumab [RoActemra/Actemra]
methotrexate
placebo
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
Inclusion Criteria:
- adult patients, ≥ 18 years of age;
- moderate to severe active rheumatoid arthritis (Disease Activity Score (DAS28) > 4.4);
- inadequate response to methotrexate;
- on a stable dose of ≥ 15mg/week methotrexate for at least 6 weeks.
Exclusion Criteria:
- prior treatment with a biologic;
- Rheumatoid arthritis (RA) functional class IV;
- known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections;
- evidence of active malignant disease.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Tocilizumab + Methotrexate
Tocilizumab + Placebo
Arm Description
Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drugs (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.
Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Outcomes
Primary Outcome Measures
Percentage of Participants With Disease Activity Score 28 Joints (DAS28) Remission at Week 24
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6.
Secondary Outcome Measures
Percentage of Participants With American College of Rheumatology (ACR20) Response
ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Percentage of Participants With ACR50 Response
ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Percentage of Participants With ACR70 Response
ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Percentage of Participants With ACR90 Response
ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time to First ACR20 Response
Time in days from first administration of study drug until ACR20 response. ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time to First ACR50 Response
Time in days from first administration of study drug until ACR50 response. ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate).
Time to First ACR70 Response
Time in days from first administration of study drug until ACR70 response. ACR70 response is defined as a ≥ 70% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time to First ACR90 Response
Time in days from first administration of study drug until ACR90 response. ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Area Under Curve (AUC) DAS28
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. AUC DAS28 was averaged over study days. Analysis of Covariance was adjusted for Baseline DAS28 as a covariate and treatment group and region as fixed factors. Higher calculated AUC values are worse (indicate higher disease activity).
Percentage of Participants With Disease Activity Score 28 (DAS28) Remission
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6.
Percentage of Participants With DAS28 Low Disease Activity (LDAS)
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. LDAS is defined as DAS28 ≤ 3.2.
Change From Baseline in DAS28 Score
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A higher value indicated higher disease activity. A negative change from Baseline indicated improvement.
Percentage of Participants With Good or Moderate European League (EULAR) DAS28 Responses
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement.
European League Against Rheumatism (EULAR) Good response: DAS28 ≤ 3.2 or a change from Baseline < -1.2.
EULAR Moderate response: DAS28 > 3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2.
Change From Baseline in Swollen Joint Count
66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement.
Change From Baseline in Tender Joint Count
68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement.
Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (VAS)
The patients global assessment of disease activity was assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Change From Baseline in Physician Global Assessment of Disease Activity Visual Analog Scale (VAS)
The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Change From Baseline in Patient Global Assessment of Pain (VAS)
The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change from Baseline indicated improvement.
Change From Baseline in Erythrocyte Sedimentation Rate (ESR)
Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeters/hour (mm/hr). A reduction in the level is considered an improvement.
Change From Baseline in C-Reactive Protein (CRP)
Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The serum concentration of CRP was measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement.
Change From Baseline in the Health Assessment Questionnaire Disability Index
The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement.
Change From Baseline in Total Genant Modified Sharp Scores (GSS)
Radiographs were taken of each hand and foot at Baseline, Weeks 24, 52 and104 and were evaluated using the Genant modified method according to Sharp. Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Joint Narrowing Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum total erosion score in the hands is 98 and in the feet 42. The maximum scores for joint space narrowing (JSN) in the hands was104 and in the feet 48. The total score was the sum of scores for erosions and JSN. The maximum total modified GSS was 292. A lower number change from Baseline was better. Analysis of covariance model, with Baseline DAS28 as a covariate and treatment and site as fixed factors.
Change From Baseline in Joint Space Narrowing Score
A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum scores for joint space narrowing (JSN) in the hands was 104 and in the feet 48 for a total possible score of 0 to 152. A lower change from Baseline indicated a better score. Analysis of covariance model included baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Change From Baseline in Erosion Score
A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. The maximum erosion score in the hands was 98 and in the feet 42 for a total possible score of 0 to 140. A lower number change from Baseline indicated a better score.
Percentage of Participants Discontinuing Tocilizumab Due to Remission
The percentage of participants who stopped treatment with tocilizumab due to remission.
Percentage of Participants Who Withdrew Due to Lack of Sufficient Therapeutic Response
Lack of Sufficient Therapeutic Response was defined as the patient not responding to the drug as expected.
Percentage of Participants Who Withdrew Due to Safety Reasons
Safety reasons were defined as adverse events, intercurrent illness or death. An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.
Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL)
The RAQoL is a disease specific patient-reported outcome measure that determines the effect rheumatoid arthritis has on a patient's quality of life consisting of 30 questions that are answered either yes=1 or no=0 for a total possible score ranging from 0 (best) to 30 (worst). A negative change from Baseline indicated improvement.
Change From Baseline in Academic Medical Center (AMC) Linear Disability Scale (ALDS)
The Academic Medical Center (AMC) Linear Disability Score (ALDS) evaluates the participant's ability to perform activities of daily life consisting of 77 questions answered yes or no . The question difficulty and the patient's ability are arranged on a single hierarchical linear scale. ALDS scores range from 10 to 90 with a higher score representing higher functional status. A positive change from Baseline indicated improvement.
Area Under the Curve (AUC) From Baseline to Week 24 for ACR Response
ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 0=no pain to 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]. Area under the curve for ACR response to Week 24 was averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (≤ 5.5 and > 5.5) as fixed factors.
Area Under the Curve (AUC) From Baseline to Week 52 for ACR Response
ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 0=no pain to 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].Area under the curve for ACR response to Week 52 averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (<=5.5 and >5.5) as fixed factors.
Time to Tocilizumab Remission
The time in days from initial study drug treatment to tocilizumab remission that occurred when the patient discontinued treatment with tocilizumab.
Time to Drug-Free Remission
The time in days from initial study drug treatment to drug free remission that occurred when the participant was able to discontinue tocilizumab, methotrexate/placebo and open label disease-modifying antirheumatic drugs (DMARDS).
Time to Flare After Tocilizumab Remission
The time in days to a flare (recurrence of disease symptoms) after the patient discontinued treatment with tocilizumab.
Time to Restart of Treatment After Discontinuation/Remission
The time in days from treatment discontinuation or remission to the restart of treatment.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00810199
Brief Title
A Study of Tocilizumab and Methotrexate Treatment Strategies (Adding Tocilizumab to Methotrexate Versus Switching to Tocilizumab) in Patients With Active Rheumatoid Arthritis With Inadequate Response to Prior Methotrexate Treatment
Official Title
Randomized Placebo-controlled Study of Two Treatment Strategies Based on Tocilizumab (TCZ) With or Without Methotrexate (MTX) and Possible Addition of Other Disease-modifying Anti-rheumatic Drugs (DMARDs) in Patients...
Study Type
Interventional
2. Study Status
Record Verification Date
July 2014
Overall Recruitment Status
Completed
Study Start Date
March 2009 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
January 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
This 2 arm study will compare 2 treatment strategies based on tocilizumab in combination with methotrexate or placebo in patients with moderate to severe rheumatoid arthritis. Patients receiving methotrexate treatment will be randomized to receive either a) tocilizumab 8 mg intravenous (iv) every 4 weeks + methotrexate orally (po) weekly or b) tocilizumab 8 mg iv every 4 weeks + placebo po weekly. After the first 24 weeks of blinded treatment, treatment adjustments (increase or decrease of treatment intensity) may be introduced at intervals, based on response. The anticipated time on study treatment is up to 3 years, and the target sample size is approximately 470 patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
556 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tocilizumab + Methotrexate
Arm Type
Experimental
Arm Description
Tocilizumab 8 mg/kg (up to 800 mg) intravenous (IV) once every 4 weeks + weekly oral methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drugs (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded methotrexate if a flare occurred.
Arm Title
Tocilizumab + Placebo
Arm Type
Placebo Comparator
Arm Description
Tocilizumab 8 mg/kg (up to 800 mg) IV once every 4 weeks + weekly oral placebo to methotrexate continuing at the patient's pre-study dose for 24 weeks. Patients taking oral corticosteroids remained on their pre-study dose (up to 10 mg/day). Week 24 to Week 52 the dose of tocilizumab and placebo to methotrexate remained the same. Based on DAS28 assessments, corticosteroid dose was adjusted and disease-modifying antirheumatic drug (DMARDS) added. Week 52 to Week 104, based on the DAS28 assessment, treatment was adjusted to one of four protocol specified treatment regimens: Treatment tapering, Continued treatment, Treatment intensification or Maintenance treatment. After Week 100, patients who discontinued tocilizumab because of remission were retreated with the last effective dose of tocilizumab or blinded placebo to methotrexate if a flare occurred.
Intervention Type
Drug
Intervention Name(s)
tocilizumab [RoActemra/Actemra]
Other Intervention Name(s)
RoActemra/Actemra
Intervention Description
tocilizumab 8 mg IV every 4 weeks.
Intervention Type
Drug
Intervention Name(s)
methotrexate
Intervention Description
Approximately 15-17 mg methotrexate capsule orally once a week.
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
Placebo matching methotrexate capsule taken orally once a week.
Primary Outcome Measure Information:
Title
Percentage of Participants With Disease Activity Score 28 Joints (DAS28) Remission at Week 24
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6.
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
Percentage of Participants With American College of Rheumatology (ACR20) Response
Description
ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
Baseline, Weeks 24, 52, 104
Title
Percentage of Participants With ACR50 Response
Description
ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
Baseline, Weeks 24, 52, 104
Title
Percentage of Participants With ACR70 Response
Description
ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
Baseline, Weeks 24, 52, 104
Title
Percentage of Participants With ACR90 Response
Description
ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
Baseline, Weeks 24, 52, 104
Title
Time to First ACR20 Response
Description
Time in days from first administration of study drug until ACR20 response. ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
104 Weeks
Title
Time to First ACR50 Response
Description
Time in days from first administration of study drug until ACR50 response. ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate).
Time Frame
104 Weeks
Title
Time to First ACR70 Response
Description
Time in days from first administration of study drug until ACR70 response. ACR70 response is defined as a ≥ 70% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
104 Weeks
Title
Time to First ACR90 Response
Description
Time in days from first administration of study drug until ACR90 response. ACR90 response is defined as a ≥ 90% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
Time Frame
104 Weeks
Title
Area Under Curve (AUC) DAS28
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. AUC DAS28 was averaged over study days. Analysis of Covariance was adjusted for Baseline DAS28 as a covariate and treatment group and region as fixed factors. Higher calculated AUC values are worse (indicate higher disease activity).
Time Frame
Baseline to Week 24
Title
Percentage of Participants With Disease Activity Score 28 (DAS28) Remission
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6.
Time Frame
Week 52
Title
Percentage of Participants With DAS28 Low Disease Activity (LDAS)
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. LDAS is defined as DAS28 ≤ 3.2.
Time Frame
Weeks 24, 52
Title
Change From Baseline in DAS28 Score
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A higher value indicated higher disease activity. A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Percentage of Participants With Good or Moderate European League (EULAR) DAS28 Responses
Description
The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement.
European League Against Rheumatism (EULAR) Good response: DAS28 ≤ 3.2 or a change from Baseline < -1.2.
EULAR Moderate response: DAS28 > 3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2.
Time Frame
Baseline, 24, 52
Title
Change From Baseline in Swollen Joint Count
Description
66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Tender Joint Count
Description
68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Patient Global Assessment of Disease Activity Visual Analog Scale (VAS)
Description
The patients global assessment of disease activity was assessed on a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Physician Global Assessment of Disease Activity Visual Analog Scale (VAS)
Description
The physician global assessment of disease activity was assessed using a 0 to 100 mm horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as "maximum disease activity" (maximum arthritis disease activity). A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Patient Global Assessment of Pain (VAS)
Description
The patient assessed their pain using a 0 to 100 millimeter (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as "no pain" and the right-hand extreme equals 100 mm as "unbearable pain". A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Erythrocyte Sedimentation Rate (ESR)
Description
Blood was collected for Erythrocyte Sedimentation Rate (ESR) (a test that assesses tissue inflammation) and was analyzed at a local laboratory. ESR was measured in millimeters/hour (mm/hr). A reduction in the level is considered an improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in C-Reactive Protein (CRP)
Description
Blood was collected for C-Reactive Protein (CRP) (a test for analysis of inflammatory and infectious disorders) and was analyzed at a central laboratory. The serum concentration of CRP was measured in milligrams/deciliter (mg/dL). A reduction in the level is considered an improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in the Health Assessment Questionnaire Disability Index
Description
The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis, consisting of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. There are 4 possible responses for each question: 0=without any difficulty, 1=with some difficulty, 2=with much difficulty and 3=unable to do. The score for each of the domains is the highest (worst) score in each domain. A patient must have a domain score for at least 6 of 8 domains to calculate a valid HAQ-DI score which is the sum of domain scores, divided by the number of domains that have a score for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52
Title
Change From Baseline in Total Genant Modified Sharp Scores (GSS)
Description
Radiographs were taken of each hand and foot at Baseline, Weeks 24, 52 and104 and were evaluated using the Genant modified method according to Sharp. Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Joint Narrowing Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum total erosion score in the hands is 98 and in the feet 42. The maximum scores for joint space narrowing (JSN) in the hands was104 and in the feet 48. The total score was the sum of scores for erosions and JSN. The maximum total modified GSS was 292. A lower number change from Baseline was better. Analysis of covariance model, with Baseline DAS28 as a covariate and treatment and site as fixed factors.
Time Frame
Baseline, Weeks 24, 52, 104
Title
Change From Baseline in Joint Space Narrowing Score
Description
A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). The maximum scores for joint space narrowing (JSN) in the hands was 104 and in the feet 48 for a total possible score of 0 to 152. A lower change from Baseline indicated a better score. Analysis of covariance model included baseline x-ray and DAS28 as covariates and treatment group and region as fixed effects.
Time Frame
Baseline, Weeks 24, 52, 104
Title
Change From Baseline in Erosion Score
Description
A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. The maximum erosion score in the hands was 98 and in the feet 42 for a total possible score of 0 to 140. A lower number change from Baseline indicated a better score.
Time Frame
Baseline, Weeks 24, 52, 104
Title
Percentage of Participants Discontinuing Tocilizumab Due to Remission
Description
The percentage of participants who stopped treatment with tocilizumab due to remission.
Time Frame
Weeks 52, 104
Title
Percentage of Participants Who Withdrew Due to Lack of Sufficient Therapeutic Response
Description
Lack of Sufficient Therapeutic Response was defined as the patient not responding to the drug as expected.
Time Frame
Up to 3 years
Title
Percentage of Participants Who Withdrew Due to Safety Reasons
Description
Safety reasons were defined as adverse events, intercurrent illness or death. An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.
Time Frame
Up to 3 years
Title
Change From Baseline in Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL)
Description
The RAQoL is a disease specific patient-reported outcome measure that determines the effect rheumatoid arthritis has on a patient's quality of life consisting of 30 questions that are answered either yes=1 or no=0 for a total possible score ranging from 0 (best) to 30 (worst). A negative change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 24, 52, 104
Title
Change From Baseline in Academic Medical Center (AMC) Linear Disability Scale (ALDS)
Description
The Academic Medical Center (AMC) Linear Disability Score (ALDS) evaluates the participant's ability to perform activities of daily life consisting of 77 questions answered yes or no . The question difficulty and the patient's ability are arranged on a single hierarchical linear scale. ALDS scores range from 10 to 90 with a higher score representing higher functional status. A positive change from Baseline indicated improvement.
Time Frame
Baseline, Weeks 104
Title
Area Under the Curve (AUC) From Baseline to Week 24 for ACR Response
Description
ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 0=no pain to 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]. Area under the curve for ACR response to Week 24 was averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (≤ 5.5 and > 5.5) as fixed factors.
Time Frame
Baseline to Week 24
Title
Area Under the Curve (AUC) From Baseline to Week 52 for ACR Response
Description
ACR response was defined as an improvement (reduction) compared with baseline for both total joint count-68 joints and swollen joint count-66 joints, and for three of five variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) where 0=no pain to 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where: 0=no disease activity to 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].Area under the curve for ACR response to Week 52 averaged over study days. Analysis of covariance model includes treatment group, region and baseline DAS28 (<=5.5 and >5.5) as fixed factors.
Time Frame
Baseline to Week 52
Title
Time to Tocilizumab Remission
Description
The time in days from initial study drug treatment to tocilizumab remission that occurred when the patient discontinued treatment with tocilizumab.
Time Frame
104 Weeks
Title
Time to Drug-Free Remission
Description
The time in days from initial study drug treatment to drug free remission that occurred when the participant was able to discontinue tocilizumab, methotrexate/placebo and open label disease-modifying antirheumatic drugs (DMARDS).
Time Frame
104 Weeks
Title
Time to Flare After Tocilizumab Remission
Description
The time in days to a flare (recurrence of disease symptoms) after the patient discontinued treatment with tocilizumab.
Time Frame
104 Weeks
Title
Time to Restart of Treatment After Discontinuation/Remission
Description
The time in days from treatment discontinuation or remission to the restart of treatment.
Time Frame
104 Weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
adult patients, ≥ 18 years of age;
moderate to severe active rheumatoid arthritis (Disease Activity Score (DAS28) > 4.4);
inadequate response to methotrexate;
on a stable dose of ≥ 15mg/week methotrexate for at least 6 weeks.
Exclusion Criteria:
prior treatment with a biologic;
Rheumatoid arthritis (RA) functional class IV;
known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections;
evidence of active malignant disease.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States
City
Upland
State/Province
California
ZIP/Postal Code
91786
Country
United States
City
Whittier
State/Province
California
ZIP/Postal Code
90606
Country
United States
City
Aventura
State/Province
Florida
ZIP/Postal Code
33180
Country
United States
City
Naples
State/Province
Florida
ZIP/Postal Code
34102
Country
United States
City
Orange Park
State/Province
Florida
ZIP/Postal Code
32073
Country
United States
City
Plantation
State/Province
Florida
ZIP/Postal Code
33317
Country
United States
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34239
Country
United States
City
South Miami
State/Province
Florida
ZIP/Postal Code
33143
Country
United States
City
Tamarac
State/Province
Florida
ZIP/Postal Code
33321
Country
United States
City
Eagan
State/Province
Minnesota
ZIP/Postal Code
55121
Country
United States
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89128
Country
United States
City
Mayfield
State/Province
Ohio
ZIP/Postal Code
44143
Country
United States
City
Middleburg Heights
State/Province
Ohio
ZIP/Postal Code
44130
Country
United States
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
City
West Reading
State/Province
Pennsylvania
ZIP/Postal Code
19611
Country
United States
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29601
Country
United States
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37205
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77004
Country
United States
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78217
Country
United States
City
Spokane
State/Province
Washington
ZIP/Postal Code
99204
Country
United States
City
Belo Horizonte
State/Province
MG
ZIP/Postal Code
30130-100
Country
Brazil
City
Porto Alegre
State/Province
RS
ZIP/Postal Code
90035-903
Country
Brazil
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
04026-000
Country
Brazil
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
04039-004
Country
Brazil
City
Sao Paulo
State/Province
SP
ZIP/Postal Code
05403-000
Country
Brazil
City
Rijeka
ZIP/Postal Code
51000
Country
Croatia
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
City
Frederiksberg
ZIP/Postal Code
2000
Country
Denmark
City
Hellerup
ZIP/Postal Code
2900
Country
Denmark
City
Køge
ZIP/Postal Code
4600
Country
Denmark
City
Tallinn
ZIP/Postal Code
11312
Country
Estonia
City
Tallinn
ZIP/Postal Code
13419
Country
Estonia
City
Abbeville
ZIP/Postal Code
80142
Country
France
City
Boulogne-billancourt
ZIP/Postal Code
92104
Country
France
City
Brest
ZIP/Postal Code
29609
Country
France
City
Echirolles
ZIP/Postal Code
38434
Country
France
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
City
Le Mans
ZIP/Postal Code
72037
Country
France
City
Marseille
ZIP/Postal Code
13285
Country
France
City
Marseille
ZIP/Postal Code
13385
Country
France
City
Monaco
ZIP/Postal Code
98012
Country
France
City
Nantes
ZIP/Postal Code
44035
Country
France
City
Nice
ZIP/Postal Code
06202
Country
France
City
Paris
ZIP/Postal Code
75571
Country
France
City
Paris
ZIP/Postal Code
75679
Country
France
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
City
Vandoeuvre-les-nancy
ZIP/Postal Code
54511
Country
France
City
Aachen
ZIP/Postal Code
52064
Country
Germany
City
Berlin
ZIP/Postal Code
10117
Country
Germany
City
Berlin
ZIP/Postal Code
13125
Country
Germany
City
Dresden
ZIP/Postal Code
01307
Country
Germany
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
City
Hamburg
ZIP/Postal Code
22081
Country
Germany
City
Jena
ZIP/Postal Code
07747
Country
Germany
City
Köln
ZIP/Postal Code
50924
Country
Germany
City
Muenchen
ZIP/Postal Code
80336
Country
Germany
City
Ratingen
ZIP/Postal Code
40882
Country
Germany
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
City
Athens
ZIP/Postal Code
11527
Country
Greece
City
Thessaloniki
ZIP/Postal Code
54636
Country
Greece
City
Thessaloniki
ZIP/Postal Code
54642
Country
Greece
City
Afula
ZIP/Postal Code
18101
Country
Israel
City
Beer Sheva
ZIP/Postal Code
8410101
Country
Israel
City
Haifa
ZIP/Postal Code
31048
Country
Israel
City
Haifa
ZIP/Postal Code
34354
Country
Israel
City
Haifa
ZIP/Postal Code
34362
Country
Israel
City
Kfar Saba
ZIP/Postal Code
44281
Country
Israel
City
Ramat-Gan
ZIP/Postal Code
52621
Country
Israel
City
Rishon Lezion
Country
Israel
City
Tel Aviv
ZIP/Postal Code
6423906
Country
Israel
City
Ancona
ZIP/Postal Code
60020
Country
Italy
City
Bari
ZIP/Postal Code
70124
Country
Italy
City
Perugia
ZIP/Postal Code
06122
Country
Italy
City
Prato
ZIP/Postal Code
59100
Country
Italy
City
Roma
ZIP/Postal Code
00168
Country
Italy
City
Bauska
ZIP/Postal Code
3901
Country
Latvia
City
Daugavpils
ZIP/Postal Code
5417
Country
Latvia
City
Liepaja
ZIP/Postal Code
3400
Country
Latvia
City
Riga
ZIP/Postal Code
1006
Country
Latvia
City
Riga
ZIP/Postal Code
1038
Country
Latvia
City
Riga
ZIP/Postal Code
LV-1002
Country
Latvia
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
City
Maastricht
ZIP/Postal Code
6202 AZ
Country
Netherlands
City
Nijmegen
ZIP/Postal Code
6525 GA
Country
Netherlands
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
City
Drammen
ZIP/Postal Code
3004
Country
Norway
City
Gjettum
ZIP/Postal Code
1346
Country
Norway
City
Kristiansand
ZIP/Postal Code
4604
Country
Norway
City
Lillehammer
ZIP/Postal Code
2609
Country
Norway
City
Moss
ZIP/Postal Code
1535
Country
Norway
City
Oslo
ZIP/Postal Code
0319
Country
Norway
City
Bucharest
ZIP/Postal Code
011172
Country
Romania
City
Bucuresti
ZIP/Postal Code
020983
Country
Romania
City
Barnaul
ZIP/Postal Code
656024
Country
Russian Federation
City
Ekaterinburg
ZIP/Postal Code
620102
Country
Russian Federation
City
Irkutsk
ZIP/Postal Code
664047
Country
Russian Federation
City
Izhevsk
ZIP/Postal Code
426009
Country
Russian Federation
City
Kazan
ZIP/Postal Code
420012
Country
Russian Federation
City
Khanty-Mansiysk
ZIP/Postal Code
628011
Country
Russian Federation
City
Kursk
ZIP/Postal Code
305007
Country
Russian Federation
City
Moscow
ZIP/Postal Code
115522
Country
Russian Federation
City
Novosibirsk
ZIP/Postal Code
630099
Country
Russian Federation
City
Novosibirsk
ZIP/Postal Code
630117
Country
Russian Federation
City
St Petersburg
ZIP/Postal Code
191015
Country
Russian Federation
City
Tjumen
ZIP/Postal Code
625023
Country
Russian Federation
City
UFA
ZIP/Postal Code
450005
Country
Russian Federation
City
Ulyanovsk
ZIP/Postal Code
432063
Country
Russian Federation
City
Vladivostok
ZIP/Postal Code
690105
Country
Russian Federation
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
City
Kragujevac
ZIP/Postal Code
34000
Country
Serbia
City
Niska Banja
ZIP/Postal Code
18250
Country
Serbia
City
Nova sad
ZIP/Postal Code
21000
Country
Serbia
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33006
Country
Spain
City
La Coruna
State/Province
La Coruña
ZIP/Postal Code
15006
Country
Spain
City
Santiago De Compostela
State/Province
La Coruña
ZIP/Postal Code
15706
Country
Spain
City
Leganes
State/Province
Madrid
ZIP/Postal Code
28191
Country
Spain
City
Bilbao
State/Province
Vizcaya
ZIP/Postal Code
48013
Country
Spain
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
City
Madrid
ZIP/Postal Code
28007
Country
Spain
City
Madrid
ZIP/Postal Code
28041
Country
Spain
City
Madrid
ZIP/Postal Code
28046
Country
Spain
City
Madrid
ZIP/Postal Code
28222
Country
Spain
City
Sevilla
ZIP/Postal Code
41009
Country
Spain
City
Goeteborg
ZIP/Postal Code
41345
Country
Sweden
City
Umea
ZIP/Postal Code
90185
Country
Sweden
City
Bangkok
ZIP/Postal Code
10300
Country
Thailand
City
Khon Kaen
ZIP/Postal Code
40002
Country
Thailand
City
Pathumthani
ZIP/Postal Code
12120
Country
Thailand
City
Cannock
ZIP/Postal Code
WS11 5XY
Country
United Kingdom
City
Glasgow
ZIP/Postal Code
G12 0YN
Country
United Kingdom
City
Leeds
ZIP/Postal Code
LS7 4SA
Country
United Kingdom
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
City
Newcastle-upon-Tyne
ZIP/Postal Code
NE2 4HH
Country
United Kingdom
City
Norwich
ZIP/Postal Code
NR4 7UY
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
22562983
Citation
Dougados M, Kissel K, Sheeran T, Tak PP, Conaghan PG, Mola EM, Schett G, Amital H, Navarro-Sarabia F, Hou A, Bernasconi C, Huizinga TW. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013 Jan;72(1):43-50. doi: 10.1136/annrheumdis-2011-201282. Epub 2012 May 5.
Results Reference
result
PubMed Identifier
24473673
Citation
Dougados M, Kissel K, Conaghan PG, Mola EM, Schett G, Gerli R, Hansen MS, Amital H, Xavier RM, Troum O, Bernasconi C, Huizinga TW. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis. 2014 May;73(5):803-9. doi: 10.1136/annrheumdis-2013-204761. Epub 2014 Jan 28.
Results Reference
result
PubMed Identifier
26037777
Citation
Dougados M, Huizinga TW, Choy EH, Bingham CO 3rd, Aassi M, Bernasconi C. Evaluation of the Disease Activity Score in Twenty-Eight Joints-Based Flare Definitions in Rheumatoid Arthritis: Data From a Three-Year Clinical Trial. Arthritis Care Res (Hoboken). 2015 Dec;67(12):1762-6. doi: 10.1002/acr.22633.
Results Reference
derived
PubMed Identifier
25169728
Citation
Huizinga TW, Conaghan PG, Martin-Mola E, Schett G, Amital H, Xavier RM, Troum O, Aassi M, Bernasconi C, Dougados M. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Ann Rheum Dis. 2015 Jan;74(1):35-43. doi: 10.1136/annrheumdis-2014-205752. Epub 2014 Aug 28.
Results Reference
derived
Learn more about this trial
A Study of Tocilizumab and Methotrexate Treatment Strategies (Adding Tocilizumab to Methotrexate Versus Switching to Tocilizumab) in Patients With Active Rheumatoid Arthritis With Inadequate Response to Prior Methotrexate Treatment
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