A Study to Assess the Effect of Tocilizumab + Methotrexate on Prevention of Structural Joint Damage in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)
A Randomized, Double-blind Study of Safety and Prevention of Structural Joint Damage During Treatment With Tocilizumab Versus Placebo, in Combination With Methotrexate, in Patients With Moderate to Severe Rheumatoid Arthritis
1 other identifier
interventional
1,196
16 countries
152
Brief Summary
This 3 arm study will compare the safety and efficacy, with respect to a reduction in signs and symptoms and prevention of joint damage, of tocilizumab versus placebo, both in combination with methotrexate (MTX) in patients with moderate to severe active rheumatoid arthritis. Patients will be randomized to receive tocilizumab 4 mg/kg IV, tocilizumab 8 mg/kg IV or placebo IV, every 4 weeks. All patients will also receive methotrexate, 10-25 mg/week. The anticipated time on study treatment is 1-2 years and the target sample size is 500+ individuals. After completion of the 2 year study participants could participate in the optional 3 year open label extension phase (year 3 to 5).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3 rheumatoid-arthritis
Started Jan 2005
Longer than P75 for phase_3 rheumatoid-arthritis
152 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
January 1, 2005
CompletedFirst Submitted
Initial submission to the registry
March 25, 2005
CompletedFirst Posted
Study publicly available on registry
March 28, 2005
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 1, 2007
CompletedResults Posted
Study results publicly available
June 7, 2011
CompletedStudy Completion
Last participant's last visit for all outcomes
July 1, 2012
CompletedFebruary 6, 2014
December 1, 2013
2.3 years
March 25, 2005
February 9, 2010
December 18, 2013
Conditions
Outcome Measures
Primary Outcomes (5)
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.
Baseline, Week 24
Change From Baseline in Modified Total Sharp-Genant Score at Week 52
Radiographs were taken of each hand and foot at Baseline and Week 52 and evaluated at a central reading service by two independent radiologists 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 100 (normalized from 98) and in the feet 42, the maximum scores for joint space narrowing in the hands is 100 (normalized from 104) and in the feet 48. The maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score.
Baseline, Week 52
Change in Physical Function as Measured by the Area Under the Curve (AUC) for the Change From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 52
HAQ-DI consisted of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities rated on a 4-point scale where 0=without any difficulty to 3=unable to do. The sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst). Functional disability was determined as a cumulative measure of HAQ-DI over 1 year by using the AUC of the change from baseline in HAQ-DI score through week 52. Decreases in AUC of change from baseline in HAQ-DI indicate a greater average improvement in physical function over time and represent a decrease in sustained impairment. For patients with missing week 52 HAQ-DI score, the AUC of the change from baseline was standardized to 52 weeks using the latest timepoint available for calculation of the AUC. The mean was adjusted for region. A negative change from baseline indicated improvement.
Baseline to Week 52
Change From Baseline in the Modified Total Sharp-Genant Score at Week 104
Radiographs of each hand and foot were taken at Baseline and Week 104 and evaluated at a central reading service by two independent radiologists 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 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 100 and in the feet 42, the maximum scores for joint space narrowing in the hands is 100 and in the feet 48. The maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score.
Baseline, Week 104
Change in Physical Function as Measured by the Area Under the Curve for the Change From Baseline in the Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 104
HAQ-DI consisted of 20 questions in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities rated on a 4-point scale where 0=without any difficulty to 3=unable to do. The sum of scores was divided by the number of domains with a score for a total possible score of 0 (best) to 3 (worst). Functional disability was determined as a cumulative measure of HAQ-DI over 2 years by using the AUC of the change from baseline in HAQ-DI score through week 104. Decreases in AUC of change from baseline in HAQ-DI indicated a gr eater average improvement in physical function over time and represent a decrease in sustained impairment. For patients with missing week 104 HAQ-DI score, the AUC of the change from baseline was standardized to 104 weeks using the latest timepoint available for calculation of the AUC. A negative change from baseline indicated improvement.
Baseline to Week 104
Secondary Outcomes (100)
Percentage of Participants With ACR50 Response
Baseline, Week 24
Percentage of Participants With ACR70 Response
Baseline,Week 24
Swollen Joint Count (66 Joint Count): Mean Change From Baseline at Week 24
Baseline, Week 24
Tender Joint Count (68 Joint Count): Mean Change From Baseline at Week 24
Baseline, Week 24
Patient's Global Visual Analog Scale (VAS): Mean Change From Baseline at Week 24
Baseline, Week 24
- +95 more secondary outcomes
Study Arms (3)
Tocilizumab 4 mg/kg + Methotrexate
EXPERIMENTALTocilizumab 4 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Tocilizumab 8 mg/kg + Methotrexate
EXPERIMENTALTocilizumab 8 mg/kg IV every 4 weeks plus MTX 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Placebo + Methotrexate
PLACEBO COMPARATORPlacebo intravenously (IV) every 4 weeks plus methotrexate (MTX) 10-25 mg (oral or parenteral) weekly for 52 weeks. From Week 16 participants with \< 20% improvement in swollen and tender joints counts were eligible for escape therapy with tocilizumab. After Week 52 participants were able to switch to open label treatment with tocilizumab 8 mg/kg every 4 weeks for 12 months in year 2 (except patients who had a \>70% improvement in both swollen and tender joint counts who remained on blinded treatment). Participants who completed year 2 of the study were eligible to enter an optional open-label long-term extension period (Year 3 to 5) and received Tocilizumab 8 mg/kg every 4 weeks.
Interventions
4 mg/kg or 8 mg/kg IV/month every 4 weeks.
10-25 mg/week
Eligibility Criteria
You may qualify if:
- adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
- inadequate response to a stable dose of MTX;
- patients of reproductive potential must be using reliable methods of contraception.
You may not qualify if:
- major surgery (including joint surgery) within 8 weeks before entering study, or planned surgery within 6 months after entering study;
- prior treatment failure with an anti-tumor necrosis factor agent;
- women who are pregnant or breast-feeding.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (152)
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Birmingham, Alabama, 35233-7333, United States
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Huntsville, Alabama, 35801, United States
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Scottsdale, Arizona, 85251, United States
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Tucson, Arizona, 85724, United States
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Anaheim, California, 92801, United States
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Long Beach, California, 90806, United States
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Los Angeles, California, 90095, United States
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San Diego, California, 92108, United States
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San Francisco, California, 94118, United States
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Santa Maria, California, 93454, United States
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Torrance, California, 90505, United States
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Boulder, Colorado, 80304, United States
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Colorado Springs, Colorado, 80910, United States
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Denver, Colorado, 80230, United States
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Aventura, Florida, 33180, United States
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Fort Lauderdale, Florida, 33334, United States
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Tampa, Florida, 33614, United States
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West Palm Beach, Florida, 33407, United States
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Boise, Idaho, 83702, United States
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Coeur d'Alene, Idaho, 83814, United States
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Idaho Falls, Idaho, 83404, United States
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Meridan, Idaho, 83642, United States
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Chicago, Illinois, 60612-3824, United States
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Rockford, Illinois, 61103, United States
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Indianapolis, Indiana, 46202-5100, United States
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Lexington, Kentucky, 40515, United States
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Frederick, Maryland, 21702, United States
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Hagerstown, Maryland, 21740, United States
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Wheaton, Maryland, 20902, United States
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St Louis, Missouri, 63131, United States
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St Louis, Missouri, 63141, United States
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Billings, Montana, 59101, United States
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Missoula, Montana, 59802, United States
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Reno, Nevada, 89502, United States
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Dover, New Hampshire, 03820, United States
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Medford, New Jersey, 08055, United States
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Voorhees Township, New Jersey, 08043, United States
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Albany, New York, 12206, United States
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Brooklyn, New York, 11201, United States
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Lake Success, New York, 11042, United States
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New York, New York, 10016, United States
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Stony Brook, New York, 11794-8161, United States
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Asheville, North Carolina, 28801, United States
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Charlotte, North Carolina, 28211, United States
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Raleigh, North Carolina, 27609, United States
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Wilmington, North Carolina, 28401, United States
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Canton, Ohio, 44718, United States
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Oklahoma City, Oklahoma, 73109, United States
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Tulsa, Oklahoma, 74135, United States
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Eugene, Oregon, 97401, United States
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Bethlehem, Pennsylvania, 18015, United States
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Duncansville, Pennsylvania, 16635, United States
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Philadelphia, Pennsylvania, 19140, United States
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Wyomissing, Pennsylvania, 19610, United States
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Columbia, South Carolina, 29204, United States
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Nashville, Tennessee, 37203, United States
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Dallas, Texas, 75231, United States
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San Antonio, Texas, 78217, United States
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Olympia, Washington, 98502, United States
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Seattle, Washington, 98104, United States
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Glendale, Wisconsin, 53217, United States
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Adelaide, 5011, Australia
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Malvern, 3144, Australia
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Melbourne, 3168, Australia
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New Lambton, 2305, Australia
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Shenton Park, 6008, Australia
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St Leonards, 2139, Australia
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Porto Alegre, 91350-200, Brazil
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Rio de Janeiro, 20551-030, Brazil
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São Paulo, 01221-020, Brazil
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São Paulo, 04026-000, Brazil
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São Paulo, 5403900, Brazil
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Beijing, 100032, China
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Beijing, 100044, China
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Nanjing, 210008, China
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Shanghai, 200127, China
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Shanghai, 200433, China
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Hellerup, 2900, Denmark
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Odense, 5000, Denmark
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Heinola, 18120, Finland
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Helsinki, 00290, Finland
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Oulu, 90029, Finland
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Vantaa, 01400, Finland
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Amiens, 80054, France
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Bobigny, 93009, France
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Bois-Guillaume, 76233, France
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Bordeaux, 33076, France
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Le Kremlin-Bicêtre, 94270, France
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Lille, 59037, France
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Nice, 06202, France
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Orléans, 45000, France
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Paris, 75651, France
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Paris, 75877, France
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Strasbourg, 67098, France
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Toulouse, 31059, France
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Vandœuvre-lès-Nancy, 54511, France
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Athens, 11527, Greece
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Athens, 15121, Greece
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Athens, 15127, Greece
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Heraklion, 71110, Greece
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Brescia, 25123, Italy
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Coppito, 67100, Italy
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Florence, 50139, Italy
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Genova, 16132, Italy
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Milan, 20122, Italy
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Milan, 20157, Italy
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Napoli, 80131, Italy
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Padua, 35128, Italy
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Pavia, 27100, Italy
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Pisa, 56100, Italy
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Reggio Emilia, 42100, Italy
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Roma, 00161, Italy
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Torino, 10128, Italy
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Udine, 33100, Italy
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Valeggio sul Mincio, 37067, Italy
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Varese, 21100, Italy
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Verona, 37134, Italy
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Chihuahua City, 31000, Mexico
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Mexico City, 03100, Mexico
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Mexico City, 06700, Mexico
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Mexico City, 06726, Mexico
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Mexico City, 07360, Mexico
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Monterrey, 64460, Mexico
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Obregón, 85000, Mexico
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Haugesund, 5528, Norway
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Lillehammer, 2609, Norway
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Tromsø, 9038, Norway
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Bydgoszcz, 85-168, Poland
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Działdowo, 13-200, Poland
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Elblag, 82-300, Poland
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Kalisz, 62-800, Poland
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Krakow, 30-119, Poland
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Krakow, 30-510, Poland
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Poznan, 60-218, Poland
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Szczecin, 71-252, Poland
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Ustroń, 43-450, Poland
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Warsaw, 00-909, Poland
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Warsaw, 02-637, Poland
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Ponce, 00716, Puerto Rico
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San Juan, 00936-5067, Puerto Rico
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Cape Town, 4001, South Africa
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Cape Town, 7405, South Africa
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Cape Town, 7500, South Africa
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Diepkloof, 1862, South Africa
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Barcelona, 08036, Spain
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Cadiz, 11009, Spain
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Mérida, 97500, Spain
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Sabadell, 08208, Spain
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Santander, 39008, Spain
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Seville, 41009, Spain
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Lausanne, 1011, Switzerland
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Sankt Gallen, 9007, Switzerland
Related Publications (8)
Khawaja MN, Bergman MJ, Yourish J, Pei J, Reiss W, Keystone E. Routine Assessment of Patient Index Data 3 and the American College of Rheumatology/European League Against Rheumatism Provisional Remission Definitions as Predictors of Radiographic Outcome in a Rheumatoid Arthritis Clinical Trial With Tocilizumab. Arthritis Care Res (Hoboken). 2017 May;69(5):609-615. doi: 10.1002/acr.23008. Epub 2017 Apr 7.
PMID: 27564431DERIVEDKremer JM, Blanco R, Halland AM, Brzosko M, Burgos-Vargas R, Mela CM, Rowell L, Fleischmann RM. Clinical efficacy and safety maintained up to 5 years in patients with rheumatoid arthritis treated with tocilizumab in a randomised trial. Clin Exp Rheumatol. 2016 Jul-Aug;34(4):625-33. Epub 2016 Apr 15.
PMID: 27087059DERIVEDBay-Jensen AC, Platt A, Siebuhr AS, Christiansen C, Byrjalsen I, Karsdal MA. Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study. Arthritis Res Ther. 2016 Jan 20;18:13. doi: 10.1186/s13075-015-0913-x.
PMID: 26787505DERIVEDKeystone EC, Anisfeld A, Ogale S, Devenport JN, Curtis JR. Continued benefit of tocilizumab plus disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis and inadequate clinical responses by week 8 of treatment. J Rheumatol. 2014 Feb;41(2):216-26. doi: 10.3899/jrheum.130489. Epub 2014 Jan 15.
PMID: 24429164DERIVEDSiebuhr AS, Bay-Jensen AC, Leeming DJ, Plat A, Byrjalsen I, Christiansen C, van de Heijde D, Karsdal MA. Serological identification of fast progressors of structural damage with rheumatoid arthritis. Arthritis Res Ther. 2013 Aug 14;15(4):R86. doi: 10.1186/ar4266.
PMID: 23945134DERIVEDFleischmann RM, Halland AM, Brzosko M, Burgos-Vargas R, Mela C, Vernon E, Kremer JM. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol. 2013 Feb;40(2):113-26. doi: 10.3899/jrheum.120447. Epub 2013 Jan 15.
PMID: 23322466DERIVEDWang J, Bansal AT, Martin M, Germer S, Benayed R, Essioux L, Lee JS, Begovich A, Hemmings A, Kenwright A, Taylor KE, Upmanyu R, Cutler P, Harari O, Marchini J, Criswell LA, Platt A. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
PMID: 22491018DERIVEDKremer JM, Blanco R, Brzosko M, Burgos-Vargas R, Halland AM, Vernon E, Ambs P, Fleischmann R. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011 Mar;63(3):609-21. doi: 10.1002/art.30158.
PMID: 21360490DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Medical Communications
- Organization
- Hoffmann-La Roche
Study Officials
- STUDY DIRECTOR
Clinical Trials
Hoffmann-La Roche
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- DOUBLE
- Who Masked
- PARTICIPANT, INVESTIGATOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
March 25, 2005
First Posted
March 28, 2005
Study Start
January 1, 2005
Primary Completion
May 1, 2007
Study Completion
July 1, 2012
Last Updated
February 6, 2014
Results First Posted
June 7, 2011
Record last verified: 2013-12