Efficacy and Safety of Adalimumab in Patients With Active Rheumatoid Arthritis Treated Concomitantly With Methotrexate.
- Conditions
- Rheumatoid Arthritis
- Interventions
- Biological: AdalimumabDrug: Placebo
- Registration Number
- NCT00195702
- Lead Sponsor
- Abbott
- Brief Summary
The purpose of the study was to assess the safety, immunogenicity, and clinical efficacy of adalimumab compared with placebo (during double-blind phase) and to to evaluate the long-term safety and maintenance of efficacy following repeated administration of adalimumab (during open-label extension phase) in patients with persistently active rheumatoid arthritis who were receiving concurrent methotrexate therapy.
- Detailed Description
This was a 10-year study which had an initial 52-week, double-blind, placebo-controlled phase followed by an open-label extension phase up to 9 years in duration. Data were analyzed for the double-blind phase using all patients who were randomized and received at least one dose of study drug through Week 52 and for all patients who received at least one dose of adalimumab during the 10-year study (the Intent-to-Treat \[ITT\] population).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 619
- Age 18 or older and in good health (Investigator discretion) with a recent stable medical history
- Met American College of Rheumatology (ACR) criteria for diagnosis of active rheumatoid arthritis (RA) and had at both screening and baseline visits >=6 swollen joints and >=9 tender joints, despite a minimum of 3-months treatment with methotrexate (MTX). (Distal interphalangeal joints [DIPs] were not to be included in joint count for inclusion. The screening and baseline visits could be 3 to 28 days apart for patients not previously receiving disease-modifying anti-rheumatic drugs [DMARDs] other than MTX or 4 to 6 weeks for patients requiring a DMARD washout period.)
- Insufficient efficacy with MTX 12.5 to 25 mg per week (10 mg per week if MTX intolerant).
- If patient on a second-line treatment (DMARD) other than MTX, he/she had to discontinue it for at least 28 days before the baseline visit (the washout period).
- Treatment with oral folic acid 1-3 mg/day or, if appropriate, up to 10 mg leucovorin per week.
- Both rheumatoid factor positivity and a C-reactive protein value >=1 mg/dL, or at least one joint erosion on X-ray.
- Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study.
- Female subject who was pregnant or breast-feeding or considering becoming pregnant.
- Preceding treatment with any tumor necrosis factor (TNF) antagonist, including adalimumab.
- Prior exposure to alkylating agents, such as chlorambucil or cyclophosphamide.
- Intra-articular, intramuscular, or intravenous administration of corticosteroids within 4 weeks prior to the screening visit.
- Subject was wheelchair bound or bedridden.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description DB adalimumab 20 mg ew Adalimumab Subjects received 20 mg adalimumab subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase. DB adalimumab 40 mg eow Adalimumab Subjects received 40 mg adalimumab subcutaneously (SC) every other week (eow) and concomitant methotrexate (MTX) during the double-blind (DB) phase. Subjects received placebo injections SC and concomitant MTX on the alternate weeks during the DB phase. DB placebo ew Placebo Subjects received placebo subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase. DB adalimumab 20 mg ew/OL adalimumab 40 mg eow Adalimumab Subjects received adalimumab 20 mg subcutaneously (SC) once weekly (ew) during the double-blind (DB) phase, then adalimumab 40 mg SC every other week (eow) during the open-label (OL) extension phase, along with concomitant methotrexate (MTX). DB adalimumab 40 mg eow/OL adalimumab 40 mg eow Adalimumab Subjects received adalimumab 40 mg subcutaneously (SC) every other week (eow) with placebo on alternate weeks during the double-blind (DB) phase, then adalimumab 40 mg SC eow during the open-label (OL) extension phase, along with concomitant methotrexate (MTX). DB placebo ew/OL adalimumab 40 mg eow Adalimumab Subjects received placebo subcutaneously (SC) once weekly (ew) during the double-blind phase, then adalimumab 40 mg SC every other week (eow) during the open-label (OL) extension phase, along with concomitant methotrexate (MTX).
- Primary Outcome Measures
Name Time Method Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 24 Week 24 Patients were responders if they had: \>= 20% improvement in tender joint count; \>= 20% improvement in swollen joint count; and \>= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Change From Baseline in Modified Total Sharp X-ray Score at Week 52 Baseline and Week 52 Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 52. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 \[normal\] to 398 \[maximal disease\]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease.
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 52 Baseline and Week 52 Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement.
- Secondary Outcome Measures
Name Time Method Number of Participants Meeting ACR20 Response Criteria at Week 52 Week 52 Patients were responders if they had: \>= 20% improvement in tender joint count; \>= 20% improvement in swollen joint count; and \>= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Change From Baseline in Modified Total Sharp X-ray Score at Week 24 Baseline and Week 24 Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 24. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 \[normal\] to 398 \[maximal disease\]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease.
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 24 Baseline and Week 24 Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement.
Maintenance of the Disability Index of the HAQ at Week 52 for Participants Who Were Responders at Week 12 or Week 24 Week 52 Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Responders had a \>= 0.22-unit decrease (improvement) in HAQ scores from baseline to Week 12 or 24.
Maintenance of ACR20 Response at Week 52 for Participants Who Were ACR20 Responders at Week 24 Week 52 Patients were responders if they had: \>= 20% improvement in tender joint count; \>= 20% improvement in swollen joint count; and \>= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Number of Participants With a Continuous ACR70 Response for 6 Months During 52 Weeks of Treatment Baseline through Week 52 Patients were responders if they had: \>= 70% improvement in tender joint count; \>= 70% improvement in swollen joint count; and \>= 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Time to First Response According to ACR20 Criteria - Number of Participants Meeting ACR20 Criteria for the First Time at Each Time Point Baseline through Week 52 Patients were responders if they had: \>= 20% improvement in tender joint count; \>= 20% improvement in swollen joint count; and \>= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Time to First Response According to ACR50 Criteria - Number of Participants Meeting ACR50 Criteria for the First Time at Each Time Point Baseline through Week 52 Patients were responders if they had: \>= 50% improvement in tender joint count; \>= 50% improvement in swollen joint count; and \>= 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Time to First Response According to ACR70 Criteria - Number of Participants Meeting ACR70 Criteria for the First Time at Each Time Point Baseline through Week 52 Patients were responders if they had: \>= 70% improvement in tender joint count; \>= 70% improvement in swollen joint count; and \>= 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.
Estimated Yearly Progression of Rheumatoid Arthritis Baseline and Week 52 Estimated yearly progression was defined as modified total Sharp x-ray score at baseline divided by duration of rheumatoid arthritis disease at baseline. Actual progression during the study was defined as modified total Sharp x-ray score at Week 52 minus modified total Sharp x-ray score at baseline divided by the duration of the study. The range of scores for the modified total Sharp x-ray score was 0 (normal) to 398 (maximal disease).
Trial Locations
- Locations (87)
Site Ref # / Investigator 358
🇺🇸Voorhees, New Jersey, United States
Site Ref # / Investigator 60736
🇺🇸Anaheim, California, United States
Site Ref # / Investigator 712
🇺🇸Danbury, Connecticut, United States
Site Ref # / Investigator 2497
🇨🇦Toronto, Ontario, Canada
Site Ref # / Investigator 340
🇺🇸Greensboro, North Carolina, United States
Site Ref # / Investigator 444
🇨🇦Newmarket, Ontario, Canada
Site Ref # / Investigator 421
🇨🇦Toronto, Ontario, Canada
Site Ref # / Investigator 60732
🇺🇸Chicago, Illinois, United States
Site Ref # / Investigator 510
🇺🇸Houston, Texas, United States
Site Ref # / Investigator 509
🇺🇸Seattle, Washington, United States
Site Ref # / Investigator 512
🇺🇸Durham, North Carolina, United States
Site Ref # / Investigator 2496
🇨🇦Richmond, British Columbia, Canada
Site Ref # / Investigator 60702
🇨🇦Saskatoon, Saskatchewan, Canada
Site Ref # / Investigator 495
🇨🇦Penticton, British Columbia, Canada
Site Ref # / Investigator 470
🇺🇸Oklahoma City, Oklahoma, United States
Site Ref # / Investigator 462
🇺🇸Nashville, Tennessee, United States
Site Ref # / Investigator 465
🇺🇸Burlington, Massachusetts, United States
Site Ref # / Investigator 494
🇺🇸Wichita, Kansas, United States
Site Ref # / Investigator 730
🇺🇸Wheaton, Maryland, United States
Site Ref # / Investigator 424
🇺🇸Huntsville, Alabama, United States
Site Ref # / Investigator 467
🇺🇸Wichita, Kansas, United States
Site Ref # / Investigator 371
🇺🇸St. Louis, Missouri, United States
Site Ref # / Investigator 2508
🇺🇸Portland, Maine, United States
Site Ref # / Investigator 360
🇺🇸Escondido, California, United States
Site Ref # / Investigator 469
🇺🇸La Jolla, California, United States
Site Ref # / Investigator 60734
🇺🇸San Louis Obispo, California, United States
Site Ref # / Investigator 2512
🇺🇸Worcester, Massachusetts, United States
Site Ref # / Investigator 2510
🇺🇸Mobile, Alabama, United States
Site Ref # / Investigator 60739
🇺🇸Van Nuys, California, United States
Site Ref # / Investigator 499
🇺🇸Orlando, Florida, United States
Site Ref # / Investigator 729
🇺🇸Tampa, Florida, United States
Site Ref # / Investigator 2506
🇺🇸Indianapolis, Indiana, United States
Site Ref # / Investigator 487
🇺🇸Omaha, Nebraska, United States
Site Ref # / Investigator 463
🇺🇸Zephyrhills, Florida, United States
Site Ref # / Investigator 392
🇺🇸Baltimore, Maryland, United States
Site Ref # / Investigator 60730
🇺🇸Shawnee Mission, Kansas, United States
Site Ref # / Investigator 726
🇺🇸Springfield, Illinois, United States
Site Ref # / Investigator 731
🇺🇸Kansas City, Missouri, United States
Site Ref # / Investigator 502
🇺🇸St. Louis, Missouri, United States
Site Ref # / Investigator 364
🇺🇸Dover, New Hampshire, United States
Site Ref # / Investigator 718
🇺🇸Charleston, South Carolina, United States
Site Ref # / Investigator 60729
🇺🇸Phoenix, Arizona, United States
Site Ref # / Investigator 714
🇺🇸La Jolla, California, United States
Site Ref # / Investigator 710
🇺🇸Aventura, Florida, United States
Site Ref # / Investigator 492
🇺🇸San Jose, California, United States
Site Ref # / Investigator 725
🇺🇸Scottsdale, Arizona, United States
Site Ref # / Investigator 419
🇺🇸Palm Desert, California, United States
Site Ref # / Investigator 498
🇺🇸Dunedin, Florida, United States
Site Ref # / Investigator 732
🇺🇸South Bend, Indiana, United States
Site Ref # / Investigator 485
🇺🇸Idaho Falls, Idaho, United States
Site Ref # / Investigator 2436
🇺🇸Boise, Idaho, United States
Site Ref # / Investigator 473
🇺🇸Kalamazoo, Michigan, United States
Site Ref # / Investigator 354
🇺🇸Cumberland, Maryland, United States
Site Ref # / Investigator 482
🇺🇸St. Louis, Missouri, United States
Site Ref # / Investigator 471
🇺🇸Grand Rapids, Michigan, United States
Site Ref # / Investigator 353
🇺🇸Concord, New Hampshire, United States
Site Ref # / Investigator 483
🇺🇸Rochester, New York, United States
Site Ref # / Investigator 60726
🇺🇸Mercerville, New Jersey, United States
Site Ref # / Investigator 461
🇺🇸Raleigh, North Carolina, United States
Site Ref # / Investigator 60737
🇺🇸Salisbury, North Carolina, United States
Site Ref # / Investigator 456
🇺🇸Mayfield Village, Ohio, United States
Site Ref # / Investigator 60723
🇺🇸Oklahoma, Oklahoma, United States
Site Ref # / Investigator 422
🇺🇸Eugene, Oregon, United States
Site Ref # / Investigator 352
🇺🇸Mechanicsburg, Pennsylvania, United States
Site Ref # / Investigator 60735
🇺🇸Colmar, Pennsylvania, United States
Site Ref # / Investigator 2507
🇺🇸Duncansville, Pennsylvania, United States
Site Ref # / Investigator 717
🇺🇸East Norriton, Pennsylvania, United States
Site Ref # / Investigator 480
🇺🇸Wexford, Pennsylvania, United States
Site Ref # / Investigator 460
🇺🇸Memphis, Tennessee, United States
Site Ref # / Investigator 60724
🇺🇸Wyomissing, Pennsylvania, United States
Site Ref # / Investigator 60728
🇺🇸Galveston, Texas, United States
Site Ref # / Investigator 716
🇺🇸Austin, Texas, United States
Site Ref # / Investigator 2509
🇺🇸Houston, Texas, United States
Site Ref # / Investigator 60725
🇺🇸Falls Church, Virginia, United States
Site Ref # / Investigator 711
🇺🇸Richmond, Virginia, United States
Site Ref # / Investigator 356
🇺🇸Spokane, Washington, United States
Site Ref # / Investigator 475
🇨🇦Calgary, Alberta, Canada
Site Ref # / Investigator 60738
🇺🇸Kenosha, Wisconsin, United States
Site Ref # / Investigator 464
🇺🇸Tacoma, Washington, United States
Site Ref # / Investigator 496
🇨🇦Halifax, Nova Scotia, Canada
Site Ref # / Investigator 2495
🇨🇦Winnipeg, Manitoba, Canada
Site Ref # / Investigator 363
🇨🇦Montreal, Quebec, Canada
Site Ref # / Investigator 478
🇨🇦Toronto, Ontario, Canada
Site Ref # / Investigator 500
🇺🇸Raleigh, North Carolina, United States
Site Ref # / Investigator 60731
🇺🇸Raleigh, North Carolina, United States
Site Ref # / Investigator 491
🇺🇸Lexington, Kentucky, United States
Site Ref # / Investigator 2511
🇺🇸Wyomissing, Pennsylvania, United States