Efficacy and Safety of Adalimumab in Patients With Active Rheumatoid Arthritis Treated Concomitantly With Methotrexate.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab in Rheumatoid Arthritis Patients Currently Receiving Treatment With Methotrexate

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Biological: Adalimumab; Biological: Adalimumab; Biological: Adalimumab; Biological: Adalimumab; Biological: Adalimumab; Drug: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 619
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Site Ref # / Investigator 475
  • British Columbia
    • Penticton, British Columbia, Canada, V2A 3G8
      • Site Ref # / Investigator 495
    • Richmond, British Columbia, Canada, V7C 5L9
      • Site Ref # / Investigator 2496
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3N OK6
      • Site Ref # / Investigator 2495
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 4K4
      • Site Ref # / Investigator 496
  • Ontario
    • Newmarket, Ontario, Canada, L3Y 3R7
      • Site Ref # / Investigator 444
    • Toronto, Ontario, Canada, M4N 3M5
      • Site Ref # / Investigator 2497
    • Toronto, Ontario, Canada, M5L 3L9
      • Site Ref # / Investigator 478
    • Toronto, Ontario, Canada, M5T 2S8
      • Site Ref # / Investigator 421
  • Quebec
    • Montreal, Quebec, Canada, H3Z 2Z3
      • Site Ref # / Investigator 363
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Site Ref # / Investigator 60702
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Site Ref # / Investigator 424
    • Mobile, Alabama, United States, 36608
      • Site Ref # / Investigator 2510
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Site Ref # / Investigator 60729
    • Scottsdale, Arizona, United States, 85260
      • Site Ref # / Investigator 725
  • California
    • Anaheim, California, United States, 92801
      • Site Ref # / Investigator 60736
    • Escondido, California, United States, 92025
      • Site Ref # / Investigator 360
    • La Jolla, California, United States, 92037-0943
      • Site Ref # / Investigator 714
    • La Jolla, California, United States, 92037
      • Site Ref # / Investigator 469
    • Palm Desert, California, United States, 92260
      • Site Ref # / Investigator 419
    • San Jose, California, United States, 95126
      • Site Ref # / Investigator 492
    • San Louis Obispo, California, United States, 93405
      • Site Ref # / Investigator 60734
    • Van Nuys, California, United States, 91405
      • Site Ref # / Investigator 60739
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Site Ref # / Investigator 712
  • Florida
    • Aventura, Florida, United States, 33180
      • Site Ref # / Investigator 710
    • Dunedin, Florida, United States, 34698
      • Site Ref # / Investigator 498
    • Orlando, Florida, United States, 32806
      • Site Ref # / Investigator 499
    • Tampa, Florida, United States, 33614
      • Site Ref # / Investigator 729
    • Zephyrhills, Florida, United States, 33542
      • Site Ref # / Investigator 463
  • Idaho
    • Boise, Idaho, United States, 83704
      • Site Ref # / Investigator 2436
    • Idaho Falls, Idaho, United States, 83404
      • Site Ref # / Investigator 485
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Site Ref # / Investigator 60732
    • Springfield, Illinois, United States, 62704
      • Site Ref # / Investigator 726
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Site Ref # / Investigator 2506
    • South Bend, Indiana, United States, 46601
      • Site Ref # / Investigator 732
  • Kansas
    • Shawnee Mission, Kansas, United States, 66216
      • Site Ref # / Investigator 60730
    • Wichita, Kansas, United States, 67203
      • Site Ref # / Investigator 467
    • Wichita, Kansas, United States, 67208
      • Site Ref # / Investigator 494
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Site Ref # / Investigator 491
  • Maine
    • Portland, Maine, United States, 04102
      • Site Ref # / Investigator 2508
  • Maryland
    • Baltimore, Maryland, United States, 21239
      • Site Ref # / Investigator 392
    • Cumberland, Maryland, United States, 21502
      • Site Ref # / Investigator 354
    • Wheaton, Maryland, United States, 20902
      • Site Ref # / Investigator 730
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Site Ref # / Investigator 465
    • Worcester, Massachusetts, United States, 01610
      • Site Ref # / Investigator 2512
  • Michigan
    • Grand Rapids, Michigan, United States, 49506
      • Site Ref # / Investigator 471
    • Kalamazoo, Michigan, United States, 49009
      • Site Ref # / Investigator 473
  • Missouri
    • Kansas City, Missouri, United States, 64114
      • Site Ref # / Investigator 731
    • St. Louis, Missouri, United States, 63110
      • Site Ref # / Investigator 502
    • St. Louis, Missouri, United States, 63128
      • Site Ref # / Investigator 482
    • St. Louis, Missouri, United States, 63141
      • Site Ref # / Investigator 371
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Site Ref # / Investigator 487
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Site Ref # / Investigator 353
    • Dover, New Hampshire, United States, 03820
      • Site Ref # / Investigator 364
  • New Jersey
    • Mercerville, New Jersey, United States, 08619
      • Site Ref # / Investigator 60726
    • Voorhees, New Jersey, United States, 08043
      • Site Ref # / Investigator 358
  • New York
    • Rochester, New York, United States, 14609
      • Site Ref # / Investigator 483
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Site Ref # / Investigator 512
    • Greensboro, North Carolina, United States, 27408
      • Site Ref # / Investigator 340
    • Raleigh, North Carolina, United States, 27609
      • Site Ref # / Investigator 461
    • Raleigh, North Carolina, United States, 27609
      • Site Ref # / Investigator 500
    • Raleigh, North Carolina, United States, 27612
      • Site Ref # / Investigator 60731
    • Salisbury, North Carolina, United States, 28144
      • Site Ref # / Investigator 60737
  • Ohio
    • Mayfield Village, Ohio, United States, 44143
      • Site Ref # / Investigator 456
  • Oklahoma
    • Oklahoma, Oklahoma, United States, 73112
      • Site Ref # / Investigator 60723
    • Oklahoma City, Oklahoma, United States, 73112
      • Site Ref # / Investigator 470
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Site Ref # / Investigator 422
  • Pennsylvania
    • Colmar, Pennsylvania, United States, 18915-9671
      • Site Ref # / Investigator 60735
    • Duncansville, Pennsylvania, United States, 16635
      • Site Ref # / Investigator 2507
    • East Norriton, Pennsylvania, United States, 19401
      • Site Ref # / Investigator 717
    • Mechanicsburg, Pennsylvania, United States, 17055
      • Site Ref # / Investigator 352
    • Wexford, Pennsylvania, United States, 15090
      • Site Ref # / Investigator 480
    • Wyomissing, Pennsylvania, United States, 19610
      • Site Ref # / Investigator 2511
    • Wyomissing, Pennsylvania, United States, 19610
      • Site Ref # / Investigator 60724
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Site Ref # / Investigator 718
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Site Ref # / Investigator 460
    • Nashville, Tennessee, United States, 37205
      • Site Ref # / Investigator 462
  • Texas
    • Austin, Texas, United States, 78705
      • Site Ref # / Investigator 716
    • Galveston, Texas, United States, 77555-0759
      • Site Ref # / Investigator 60728
    • Houston, Texas, United States, 77074
      • Site Ref # / Investigator 2509
    • Houston, Texas, United States, 77074
      • Site Ref # / Investigator 510
  • Virginia
    • Falls Church, Virginia, United States, 22044
      • Site Ref # / Investigator 60725
    • Richmond, Virginia, United States, 23219
      • Site Ref # / Investigator 711
  • Washington
    • Seattle, Washington, United States, 98166-2967
      • Site Ref # / Investigator 509
    • Spokane, Washington, United States, 99204
      • Site Ref # / Investigator 356
    • Tacoma, Washington, United States, 98405
      • Site Ref # / Investigator 464
  • Wisconsin
    • Kenosha, Wisconsin, United States, 53142
      • Site Ref # / Investigator 60738

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DB adalimumab 20 mg ew; Subjects received 20 mg adalimumab subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase.	Biological: Adalimumab; Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira
Experimental: DB adalimumab 40 mg eow; 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.	Biological: Adalimumab; Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira
Placebo Comparator: DB placebo ew; Subjects received placebo subcutaneously (SC) once weekly (ew) and concomitant methotrexate (MTX) during the double-blind (DB) phase.	Drug: Placebo; Self-administered, subcutaneous injection of placebo (1.6 mL/injection) once weekly (ew) for up to 52 weeks.
Experimental: DB adalimumab 20 mg ew/OL adalimumab 40 mg eow; 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).	Biological: Adalimumab; Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira
Experimental: DB adalimumab 40 mg eow/OL adalimumab 40 mg eow; 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).	Biological: Adalimumab; Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira
Experimental: DB placebo ew/OL adalimumab 40 mg eow; 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).	Biological: Adalimumab; Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.; Other Names: ABT-D2E7; Humira; Biological: Adalimumab; Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.; Other Names: ABT-D2E7; Humira

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria at 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.	Week 24
Change From Baseline in Modified Total Sharp X-ray Score at 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.	Baseline and Week 52
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at 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.	Baseline and Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Meeting ACR20 Response Criteria at 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.	Week 52
Change From Baseline in Modified Total Sharp X-ray Score at 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.	Baseline and Week 24
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at 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.	Baseline and Week 24
Maintenance of the Disability Index of the HAQ at Week 52 for Participants Who Were Responders at Week 12 or 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). Responders had a >= 0.22-unit decrease (improvement) in HAQ scores from baseline to Week 12 or 24.	Week 52
Maintenance of ACR20 Response at Week 52 for Participants Who Were ACR20 Responders at 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.	Week 52
Number of Participants With a Continuous ACR70 Response for 6 Months During 52 Weeks of Treatment	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.	Baseline through Week 52
Time to First Response According to ACR20 Criteria - Number of Participants Meeting ACR20 Criteria for the First Time at Each Time Point	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.	Baseline through Week 52
Time to First Response According to ACR50 Criteria - Number of Participants Meeting ACR50 Criteria for the First Time at Each Time Point	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.	Baseline through Week 52
Time to First Response According to ACR70 Criteria - Number of Participants Meeting ACR70 Criteria for the First Time at Each Time Point	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.	Baseline through Week 52
Estimated Yearly Progression of Rheumatoid Arthritis	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).	Baseline and Week 52

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Measure: Gender - Female/Male - for the Any Adalimumab Through Year 10 Group (Intent-to-Treat)	Gender (female/male) recorded at Baseline for the Intent-to-Treat population (the Any Adalimumab Through Year 10 group) of the study. This measure was not included in the Baseline Characteristics section due to the difficulty of maintaining correct subject numbers and totals in that section.	Baseline for Intent-to-Treat (Any Adalimumab Through Year 10) Group
Baseline Measure: Age Categories for the Any Adalimumab Through Year 10 Group (Intent-to-Treat)	Age recorded at Baseline, reported by category, for the Intent-to-Treat population (the Any Adalimumab Through Year 10 group) of the study. This measure was not included in the Baseline Characteristics section due to the difficulty of maintaining correct subject numbers and totals in that section.	Baseline for Intent-to-Treat (Any Adalimumab Through Year 10) Group
Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 260	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.	Week 260
Number of Participants Meeting the American College of Rheumatology 20% (ACR20) Response Criteria at Week 520	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.	Week 520
Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 260	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.	Week 260
Number of Participants Meeting the American College of Rheumatology 50% (ACR50) Response Criteria at Week 520	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.	Week 520
Number of Participants Meeting the American College of Rheumatology 70% (ACR70) Response Criteria at Week 260	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.	Week 260
Number of Participants Meeting the American College of Rheumatology 70% (ACR70) Response Criteria at Week 520	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.	Week 520
Number of Participants With a Continuous American College of Rheumatology 70% (ACR70) Response for at Least 6 Months Through Year 10	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.	Baseline through Week 520
Number of Participants With at Least a 0.22 Reduction From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 260	The Health Assessment Questionnaire (HAQ) Disability Index is a self-reported measure of disability, which assesses the patient's ability to perform the following tasks: dress and groom; arise; eat; walk; reach; grip; maintain hygiene; and maintain daily activity. Possible responses/scores are 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). Negative mean changes from Baseline indicate improvement. An improvement of 0.22 in score (a -0.22 or greater reduction from Baseline score) is a minimally clinically significant change.	Week 260
Number of Participants With at Least a 0.22 Reduction From Baseline in the Health Assessment Questionnaire (HAQ) Disability Index at Week 520	The Health Assessment Questionnaire (HAQ) Disability Index is a self-reported measure of disability, which assesses the patient's ability to perform the following tasks: dress and groom; arise; eat; walk; reach; grip; maintain hygiene; and maintain daily activity. Possible responses/scores are 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). Negative mean changes from Baseline indicate improvement. An improvement of 0.22 in score (a -0.22 or greater reduction from Baseline score) is a minimally clinically significant change.	Week 520
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 260	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 were: 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.	Baseline and Week 260
Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 520	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 were: 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.	Baseline and Week 520
Change From Baseline in Modified Total Sharp X-ray Score at Week 416	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 416. 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.	Baseline and Week 416
Change From Baseline in Modified Total Sharp X-ray Score at Week 520	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 520. 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.	Baseline and Week 520

Collaborators and Investigators

• Sponsor: Abbott
• Investigators: Study Director: Laura Redden, MD, PhD, Abbott

Publications and helpful links

General Publications

• Burmester GR, Landewe R, Genovese MC, Friedman AW, Pfeifer ND, Varothai NA, Lacerda AP. Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Ann Rheum Dis. 2017 Feb;76(2):414-417. doi: 10.1136/annrheumdis-2016-209322. Epub 2016 Jun 23.
• Smolen J, Fleischmann R, Aletaha D, Li Y, Zhou Y, Sainsbury I, Galindo IL. Disease activity improvements with optimal discriminatory ability between treatment arms: applicability in early and established rheumatoid arthritis clinical trials. Arthritis Res Ther. 2019 Nov 10;21(1):231. doi: 10.1186/s13075-019-2005-9.
• Keystone EC, Breedveld FC, van der Heijde D, van Vollenhoven RF, Emery P, Smolen JS, Sainsbury I, Florentinus S, Kupper H, Chen K, Kavanaugh A. Achieving comprehensive disease control in patients with early and established rheumatoid arthritis treated with adalimumab plus methotrexate versus methotrexate alone. RMD Open. 2017 Sep 26;3(2):e000445. doi: 10.1136/rmdopen-2017-000445. eCollection 2017.
• Landewe R, Ostergaard M, Keystone EC, Florentinus S, Liu S, van der Heijde D. Analysis of integrated radiographic data from two long-term, open-label extension studies of adalimumab for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2015 Feb;67(2):180-6. doi: 10.1002/acr.22426.
• Emery P, Kavanaugh A, Bao Y, Ganguli A, Mulani P. Comprehensive disease control (CDC): what does achieving CDC mean for patients with rheumatoid arthritis? Ann Rheum Dis. 2015 Dec;74(12):2165-74. doi: 10.1136/annrheumdis-2014-205302. Epub 2014 Aug 19.
• Keystone EC, van der Heijde D, Kavanaugh A, Kupper H, Liu S, Guerette B, Mozaffarian N. Clinical, functional, and radiographic benefits of longterm adalimumab plus methotrexate: final 10-year data in longstanding rheumatoid arthritis. J Rheumatol. 2013 Sep;40(9):1487-97. doi: 10.3899/jrheum.120964. Epub 2013 Jul 1.
• Keystone EC, Kavanaugh A, Weinblatt ME, Patra K, Pangan AL. Clinical consequences of delayed addition of adalimumab to methotrexate therapy over 5 years in patients with rheumatoid arthritis. J Rheumatol. 2011 May;38(5):855-62. doi: 10.3899/jrheum.100752. Epub 2011 Feb 1.

Study record dates

Study Major Dates

• Study Start: February 1, 2000
• Primary Completion (Actual): September 1, 2002
• Study Completion (Actual): August 1, 2010

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Estimate): August 26, 2011
• Last Update Submitted That Met QC Criteria: August 23, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Antirheumatic Agents; Adalimumab
• Other Study ID Numbers: DE019