Efficacy and Safety of Adalimumab and Methotrexate (MTX) Versus MTX Monotherapy in Subjects With Early Rheumatoid Arthritis (PREMIER)

A Prospective Multi-Centre Randomised, Double-Blind, Active Comparator-Controlled, Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis (PREMIER).

The purpose of the study is to assess the safety and efficacy of adalimumab in combination with methotrexate in patients with recent onset rheumatoid arthritis (RA), and to assess the long-term safety and maintenance of efficacy after treatment with adalimumab for up to 10 years.

Study Overview

• Status: Completed
• Conditions: Early Rheumatoid Arthritis
• Intervention / Treatment: Biological: Adalimumab; Drug: Methotrexate; Drug: Methotrexate placebo; Biological: Adalimumab placebo

Detailed Description

This study had an initial 2-year double-blind treatment period followed by an 8-year open-label extension period, for a total of up to 10 years study duration. The study was designed to assess the potential of adalimumab + methotrexate to improve signs and symptoms of disease and to inhibit radiographic progression in patients with recent onset (disease duration less than 3 years) rheumatoid arthritis not previously treated with methotrexate. Adalimumab is a human anti-tumor necrosis factor (TNF) monoclonal antibody.

• Study Type: Interventional
• Enrollment (Actual): 799
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia, 4102
    • Site Reference ID/Investigator# 310
  • Camperdown, Australia, 2050
    • Site Reference ID/Investigator# 755
  • Clayton, Australia, 3168
    • Site Reference ID/Investigator# 337
  • Darlinghurst, Sydney, Australia, 2010
    • Site Reference ID/Investigator# 331
  • Kogarah, Australia, 2217
    • Site Reference ID/Investigator# 745
  • Maroochydore, Australia, 4558
    • Site Reference ID/Investigator# 738
  • New Lambton, Australia, 2305
    • Site Reference ID/Investigator# 335
  • Shenton Park, Australia, 6008
    • Site Reference ID/Investigator# 737
  • South Hobart, Australia, 7004
    • Site Reference ID/Investigator# 307
  • West Heidelberg, Australia, 3081
    • Site Reference ID/Investigator# 427
  • Woodville, Australia, 5011
    • Site Reference ID/Investigator# 739
• Austria
  • Vienna, Austria, 1090
    • Site Reference ID/Investigator# 344
• Belgium
  • Brussels, Belgium, 1070
    • Site Reference ID/Investigator# 753
  • Brussels, Belgium, 1090
    • Site Reference ID/Investigator# 308
  • Brussels, Belgium, 1200
    • Site Reference ID/Investigator# 752
  • Diepenbeek, Belgium, 3590
    • Site Reference ID/Investigator# 748
  • Ghent, Belgium, 9000
    • Site Reference ID/Investigator# 6136
  • Leuven, Belgium, 3000
    • Site Ref # / Investigator 98256
  • Liege, Belgium, 4000
    • Site Reference ID/Investigator# 333
• Canada
  • Edmonton, Canada, T6G 2S2
    • Site Reference ID/Investigator# 4646
  • Hamilton, Canada, L8N 1Y2
    • Site Reference ID/Investigator# 303
  • Hamilton, Canada, L8N 2B6
    • Site Reference ID/Investigator# 330
  • Montreal, Canada, H2L 1S6
    • Site Reference ID/Investigator# 4634
  • Montreal, Canada, H3Z 2Z3
    • Site Reference ID/Investigator# 311
  • Newmarket, Canada, L3Y 3R7
    • Site Reference ID/Investigator# 309
  • Pointe-Claire, Canada, H9J 3W3
    • Site Reference ID/Investigator# 304
  • Richmond, Canada, V7C 5L9
    • Site Reference ID/Investigator# 4633
  • St. John's, Canada, A1A 5E8
    • Site Reference ID/Investigator# 763
  • Toronto, Canada, M4N 3M5
    • Site Reference ID/Investigator# 4635
  • Toronto, Canada, M5L 3L9
    • Site Reference ID/Investigator# 490
  • Victoria, Canada, V8V 3P9
    • Site Reference ID/Investigator# 760
  • Winnipeg, Canada, R3N OK6
    • Site Reference ID/Investigator# 4632
  • Ontario
    • North York, Ontario, Canada, M3H 5Y8
      • Site Ref # / Investigator 98199
• Czech Republic
  • Hradec Kralove, Czech Republic, 500 05
    • Site Reference ID/Investigator# 754
  • Plzen, Czech Republic, 305 99
    • Site Reference ID/Investigator# 332
  • Prague 2, Czech Republic, 128 50
    • Site Reference ID/Investigator# 734
• Denmark
  • Grasten, Denmark, 6300
    • Site Ref # / Investigator 95878
• Finland
  • Heinola, Finland, FI-18120
    • Site Reference ID/Investigator# 6135
  • Helsinki, Finland, 00029
    • Site Ref # / Investigator 6134
• France
  • Bobigny, France, 93009
    • Site Reference ID/Investigator# 428
  • Montpellier Cedex 5, France, 34295
    • Site Reference ID/Investigator# 348
  • Paris Cedex 14, France, 75679
    • Site Reference ID/Investigator# 4650
  • Pierre Benite, France, 69310
    • Site Reference ID/Investigator# 3415
  • Rennes, France, 35056
    • Site Reference ID/Investigator# 733
  • Strasbourg, Cedex 1, France, 67098
    • Site Reference ID/Investigator# 346
• Germany
  • Berlin, Germany, 10117
    • Site Reference ID/Investigator# 4631
  • Berlin, Germany, 14059
    • Site Reference ID/Investigator# 759
  • Berlin-Buch, Germany, 13125
    • Site Reference ID/Investigator# 3417
  • Erlangen, Germany, 91054
    • Site Reference ID/Investigator# 4630
  • Freiburg, Germany, 79106
    • Site Reference ID/Investigator# 347
  • Goerlitz, Germany, 02826
    • Site Reference ID/Investigator# 742
  • Leipzig, Germany, 04103
    • Site Reference ID/Investigator# 746
  • Munich, Germany, 80336
    • Site Ref # / Investigator 98125
  • Munich, Germany, 80336
    • Site Reference ID/Investigator# 339
  • Ratingen, Germany, 40882
    • Site Reference ID/Investigator# 744
  • Vogelsang-Gommern, Germany, 39245
    • Site Reference ID/Investigator# 338
• Ireland
  • Cork, Ireland, WDQ-23-KM9
    • Site Reference ID/Investigator# 740
  • Dublin 4, Ireland
    • Site Reference ID/Investigator# 751
• Italy
  • Genoa, Italy, 16132
    • Site Ref # / Investigator 95719
  • Naples, Italy, 80131
    • Site Reference ID/Investigator# 323
  • Udine, Italy, 33100
    • Site Reference ID/Investigator# 345
  • Verona, Italy, 37134
    • Site Reference ID/Investigator# 756
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Site Reference ID/Investigator# 343
  • Leiden, Netherlands, 2333 ZA
    • Site Reference ID/Investigator# 6133
  • Maastricht, Netherlands, 6229 HX
    • Site Reference ID/Investigator# 317
  • Nijmegen, Netherlands, 6500 HB
    • Site Reference ID/Investigator# 315
• Norway
  • Osla, Norway, 0027
    • Site Ref # / Investigator 95800
  • Osla, Norway, 0370
    • Site Ref # / Investigator 95875
• Slovakia
  • Piestany, Slovakia, 92112
    • Site Reference ID/Investigator# 3426
• Spain
  • Alicante, Spain, 03010
    • Site Ref # / Investigator 96121
  • Alicante, Spain, 03010
    • Site Reference ID/Investigator# 735
  • Barcelona, Spain, 08036
    • Site Reference ID/Investigator# 1525
  • Barcelona, Spain, 08915
    • Site Reference ID/Investigator# 1528
  • Guadalajara, Spain, 19002
    • Site Reference ID/Investigator# 750
  • Madrid, Spain, 28040
    • Site Reference ID/Investigator# 1526
  • Madrid, Spain, 28040
    • Site Reference ID/Investigator# 741
  • Santiago de Compostela, Spain, 15706
    • Site Reference ID/Investigator# 390
  • Sevilla, Spain, 41014
    • Site Reference ID/Investigator# 749
• Sweden
  • Stockholm, Sweden, 113 24
    • Site Reference ID/Investigator# 728
  • Stockholm, Sweden, 171 76
    • Site Reference ID/Investigator# 2565
  • Stockholm, Sweden, SE-141 86
    • Site Reference ID/Investigator# 4638
  • Umea, Sweden, 901 84
    • Site Ref # / Investigator 96126
  • Uppsala, Sweden, 75185
    • Site Reference ID/Investigator# 747
  • Vasteras, Sweden, S-721 89
    • Site Ref # / Investigator 96120
  • Vasteras, Sweden, S-721 89
    • Site Reference ID/Investigator# 736
• Switzerland
  • Lausanne, Switzerland, 1011
    • Site Reference ID/Investigator# 334
• United Kingdom
  • Bangor, United Kingdom, LL57 2PW
    • Site Ref # / Investigator 96116
  • Cambridge, United Kingdom, CB2 0QQ
    • Site Ref # / Investigator 95877
  • Hereford, United Kingdom, HR1 2ER
    • Site Ref # / Investigator 98258
  • Leeds, United Kingdom, LS1 3EX
    • Site Ref # / Investigator 95795
  • London, United Kingdom, SE1 9RT
    • Site Ref # / Investigator 95958
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Site Ref # / Investigator 98255
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85260
      • Site Reference ID/Investigator# 322
  • California
    • La Jolla, California, United States, 92037
      • Site Ref # / Investigator 95957
    • La Jolla, California, United States, 92037
      • Site Reference ID/Investigator# 429
    • Los Angeles, California, United States, 90048
      • Site Reference ID/Investigator# 2491
  • Colorado
    • Denver, Colorado, United States, 80230
      • Site Reference ID/Investigator# 2500
  • Florida
    • Aventura, Florida, United States, 33180
      • Site Reference ID/Investigator# 762
    • Sarasota, Florida, United States, 34239
      • Site Reference ID/Investigator# 328
    • Tampa, Florida, United States, 33614
      • Site Reference ID/Investigator# 327
    • Zephyrhills, Florida, United States, 33542
      • Site Reference ID/Investigator# 325
  • Illinois
    • Rockford, Illinois, United States, 61103
      • Site Reference ID/Investigator# 302
  • Maryland
    • Cumberland, Maryland, United States, 21502
      • Site Reference ID/Investigator# 319
    • Hagerstown, Maryland, United States, 21740
      • Site Ref # / Investigator 95960
    • Wheaton, Maryland, United States, 20902
      • Site Reference ID/Investigator# 326
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605-0000
      • Site Reference ID/Investigator# 2533
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Site Reference ID/Investigator# 336
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Site Reference ID/Investigator# 318
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Site Reference ID/Investigator# 488
  • Ohio
    • Dayton, Ohio, United States, 45408
      • Site Reference ID/Investigator# 314
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Site Reference ID/Investigator# 761
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Site Reference ID/Investigator# 757
    • Lake Oswego, Oregon, United States, 97035
      • Site Reference ID/Investigator# 361
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • Site Reference ID/Investigator# 316
    • Duncansville, Pennsylvania, United States, 16635
      • Site Reference ID/Investigator# 4649
  • Texas
    • Austin, Texas, United States, 78705
      • Site Ref # / Investigator 96122
    • Austin, Texas, United States, 78705
      • Site Reference ID/Investigator# 306
    • Austin, Texas, United States, 78705
      • Site Reference ID/Investigator# 313
    • Dallas, Texas, United States, 75231
      • Site Reference ID/Investigator# 2437
    • Houston, Texas, United States, 77074
      • Site Reference ID/Investigator# 2532
    • Houston, Texas, United States, 77074
      • Site Reference ID/Investigator# 758
  • Washington
    • Spokane, Washington, United States, 99204
      • Site Reference ID/Investigator# 321
    • Yakima, Washington, United States, 98902
      • Site Reference ID/Investigator# 305

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:

• Subject was age 18 or older and in good health (Investigator discretion) with a recent stable medical history.
• Diagnosis of rheumatoid arthritis (RA) as defined by the 1987-revised American College of Rheumatology (ACR) criteria, with a disease duration less than 3 years, at least 8 swollen joints out of the 66 joints assessed, at least 10 tender joints out of the 68 joints assessed, at least 1 joint erosion or rheumatoid factor (RF) positivity, erythrocyte sedimentation rate (ESR) >= 28 mm/1h or C-reactive protein (CRP) >= 1.5 mg/dl

Exclusion Criteria:

• Chronic arthritis diagnosed before the age of 16
• Preceding treatment with MTX, cyclophosphamide, cyclosporin, azathioprine or more than 2 other disease-modifying anti-rheumatic drugs (DMARDs)
• Subject previously received anti-tumor necrosis factor (TNF) therapy
• Permanently wheelchair-bound or bedridden patients
• Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study
• Female subject who is pregnant or breast-feeding or considering becoming pregnant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adalimumab; Participants received adalimumab 40 mg subcutaneous injection once every other week and placebo to methotrexate orally once a week during the 2-year double-blind treatment phase and then adalimumab 40 mg every other week for up to 8 years in the open-label extension.	Biological: Adalimumab; Other Names: ABT-D2E7; Humira; Drug: Methotrexate placebo
Experimental: Adalimumab + methotrexate; Participants received adalimumab 40 mg subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.	Biological: Adalimumab; Other Names: ABT-D2E7; Humira; Drug: Methotrexate
Experimental: Methotrexate; Participants received placebo to adalimumab subcutaneous injection once every other week and methotrexate orally once a week at a starting dose of 7.5 mg/week (could be escalated up to 20 mg/week) during the 2-year double-blind treatment phase. Participants received adalimumab 40 mg every other week for up to 8 years in the open-label extension phase.	Drug: Methotrexate; Biological: Adalimumab placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 52	American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count;; ≥ 50% improvement in swollen joint count; and; ≥ 50% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI));Acute phase reactant value (C-Reactive Protein). Participants who withdrew early were considered non-responders.	Baseline and 52 Weeks
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52	The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 52 were scored in a blinded manner. Joints were scored for erosions on a scale from 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale from 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.	Baseline and Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52	The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.	Baseline and Week 52
Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104	American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count;; ≥ 50% improvement in swollen joint count; and; ≥ 50% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders.	Baseline and Week 104
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104	The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 104 were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.	Baseline and Week 104
Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52	The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C reactive protein, and general health were included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission.	Week 52
Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52	The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.	Baseline and Week 52
Number of Participants With Major Clinical Response After 104 Weeks of Treatment	Major clinical response was defined as an American College of Rheumatology 70% (ACR70) response for any six continuous months, over 104 weeks of treatment. A participant was a responder if the following criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count;; ≥ 70% improvement in swollen joint count; and; ≥ 70% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were non-responders.	Any 6 continuous months from Baseline to Week 104
Change From Baseline in the Mental Component of the Short Form-36 Health Status Survey (SF-36) at Week 52	The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.	Baseline and Week 52
Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Weeks 26 and 76	American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count;; ≥ 50% improvement in swollen joint count; and; ≥ 50% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders.	Baseline and Weeks 26 and 76
Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria During the Double-blind Phase	American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 20% improvement in tender joint count;; ≥ 20% improvement in swollen joint count; and; ≥ 20% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders.	Baseline and Weeks 26, 52, 76, and 104
Number of Participants Meeting American College of Rheumatology 70% (ACR70) Response Criteria During the Double-blind Phase	American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count;; ≥ 70% improvement in swollen joint count; and; ≥ 70% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Participants withdrawing early were considered non-responders.	Baseline and Weeks 26, 52, 76, and 104
Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) During the Double-blind Treatment Phase	The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.	Baseline and Weeks 12, 26, 76, and 104
Number of Participants With Improvement in the HAQ-DI Score ≥ 0.3 During the Double-blind Treatment Phase	The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability.	Baseline and Weeks 26, 52, 76, and 104
Change From Baseline in Health Utilities Index Mark 2 and Mark 3 (HUI 2/3) During the Double-blind Treatment Phase	The HUI 2/3 is an assessment of various aspects of participants' health and ability to perform various tasks on a day-to-day basis, including reading, seeing, hearing, speaking, general outlook on life, pain/discomfort, ability to walk, use of hands, memory, ability to think/solve, and ability to perform basic activities such as eating, bathing, and dressing. The HUI 2/3 is a combined 15-item questionnaire based on a recall period of the previous 4 weeks. HUI-2 and HUI-3 scores are calculated independently. The HUI-2 score includes 6 attributes: Sensation, Mobility, Emotion, Cognition, Self-Care, and Pain. The HUI-3 score is comprised of 8 attributes: Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition, and Pain. The range of each score is from 0 (dead) to 1 (perfect health). An increase from Baseline indicates improvement.	Baseline and Weeks 26, 52, and 104
Change From Baseline in the Short Form-36 Health Status Survey (SF-36) During the Double-blind Treatment Phase	The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component and items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.	Baseline and Weeks 26 and 104
Numeric American College of Rheumatology (ACR-N) During the Double-blind Treatment Phase	ACR-N is a composite, continuous variable which measures the percentage of improvement from Baseline in individual participants based on the 7 core set variables of the ACR. ACR-N is defined as the smallest percent change from Baseline of 3 measures: tender joint counts (TJC), swollen joint counts (SJC), and the median percent improvement in the 5 remaining measures (Patient's Assessment of Pain, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Health Assessment Questionnaire - Disability Index [HAQ-DI], and C-Reactive Protein). A positive ACR-N value indicates improvement; a negative ACR-N value indicates worsening; ACR-N of 0 indicates no change.	Baseline and Weeks 26, 52, 76, and 104
Change From Baseline in Disease Activity Score (DAS28) During the Double-blind Treatment Phase	The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts,; 28 swollen joint counts,; C-reactive protein, and; Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.	Baseline and Weeks 26, 52, 76, and 104
Change From Baseline in Joint Erosion Score During the Double-blind Treatment Period	Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion)to 230 (worst). A large increase in erosion score is indicative of worsening, whereas a small change or no change is indicative of inhibition of joint erosion.	Baseline and Weeks 52 and 104
Change From Baseline in Joint Space Narrowing Score During the Double-blind Treatment Period	Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joint space narrowing (JSN) scores were recorded for each hand/wrist (16 joints) and each forefoot (5 joints) on a 5-point scale (0 = no narrowing; 1 = up to 25% narrowing; 2 = 26-65% narrowing; 3 = 66-99% narrowing; and 4 = complete narrowing). Scores were summed to calculate the total score ranging from 0 (no narrowing) to 168 (maximum narrowing). A large increase in joint narrowing score is indicative of worsening, whereas a small change or no change is indicative of inhibition of JSN.	Baseline and Weeks 52 and 104
Number of Participants With No Worsening in Modified Total Sharp Score or Components During the Double-blind Treatment Phase	The number of participants with no worsening in the modified Total Sharp Score (mTSS) and in erosion and joint space narrowing (JSN) scores, where no worsening is defined as a change from Baseline of ≤ 0 in mTSS, erosion score and JSN score, at Weeks 52 and 104. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.	Baseline and Weeks 52 and 104
Number of Participants With No Erosions at Baseline and No New Erosions at Weeks 52 and 104	The number of participants with no erosions at Baseline and no erosions at Weeks 52 and 104, where no erosions and no new erosions are defined as an erosion score = 0. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion) to 230 (worst).	Baseline and Weeks 52 and 104
Number of Participants With Non-Involved Joints at Baseline and No Newly Involved Joints at Weeks 52 and 104	Number of participants with non-involved joints at Baseline and no newly involved joints at Weeks 52 and 104, where involved joints or no newly involved joints are defined as modified Total Sharp Score (mTSS) = 0. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]).	Baseline and Weeks 52 and 104
Number of Participants Meeting ACR20 Response Criteria Over 10 Years by Adalimumab Exposure	American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 20% improvement in tender joint count;; ≥ 20% improvement in swollen joint count; and; ≥ 20% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For participants randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.	Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
Number of Participants Meeting ACR50 Response Criteria Over 10 Years by Adalimumab Exposure	American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 50% improvement in tender joint count;; ≥ 50% improvement in swollen joint count; and; ≥ 50% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.	Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
Number of Participants Meeting ACR70 Response Criteria Over 10 Years by Adalimumab Exposure	American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count;; ≥ 70% improvement in swollen joint count; and; ≥ 70% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein). Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.	Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) Over 10 Years by Adalimumab Exposure	The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.	Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.
Change From Baseline in DAS28 Over 10 Years by Adalimumab Exposure	The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts,; 28 swollen joint counts,; C-reactive protein, and; Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.	Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.
Number of Participants With DAS28 < 2.6 and < 3.2 Over 10 Years by Adalimumab Exposure	The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables: 28 tender joint counts,; 28 swollen joint counts,; C-reactive protein, and; Patient's global assessment of disease activity. Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.	After 1, 2, 5, and 10 years of adalimumab exposure
Change From Baseline in Modified Total Sharp Score (mTSS) Over 10 Years	The modified TSS (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.	Baseline (prior to first study drug treatment) and Years 2 and 10
Number of Participants With No Radiographic Progression Over 10 Years	The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. The number of participants with change from Baseline ≤ 0.5 and ≤ 0 is reported as a measure of no disease progression.	Baseline (prior to first study drug treatment) and Years 2 and 10.
Composite Score of ACR50 Plus No Change in Modified Total Sharp Score		Year 10
Number of Participants With a Major Clinical Response Over 10 Years by Adalimumab Exposure	A major clinical response was defined as maintenance of an ACR70 response for at least a 6-month continuous period at any time during the study following the first dose of adalimumab. A participant was a responder if the following criteria for improvement from Baseline were met: ≥ 70% improvement in tender joint count;; ≥ 70% improvement in swollen joint count; and; ≥ 70% improvement in at least 3 of the 5 following parameters:Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);Patient's global assessment of disease activity (measured on a 100 mm VAS);Physician's global assessment of disease activity (measured on a 100 mm VAS);Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);Acute phase reactant value (C-Reactive Protein).	From the first dose of adalimumab (at Week 1 or Week 106 for patients initially randomized to methotrexate in the DB phase) to Year 10
Number of Participants With Improvement in HAQ-DI by 0.22 and 0.5 Units Over 10 Years by Adalimumab Exposure	The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A decrease in the HAQ-DI score represents an improvement in physical function; a clinically significant improvement is defined as a decrease of least 0.22 from Baseline in the HAQ-DI score. The number of participants with improvement in HAQ-DI of at least 0.22 and 0.5 units from Baseline is reported.	Baseline and Years 1, 2, 5, and 10. Baseline was the last value prior to the first dose of adalimumab. For patients randomized to the MTX arm in the DB phase, Baseline was the last visit prior to the first adalimumab dose at Week 106.

Collaborators and Investigators

• Sponsor: AbbVie (prior sponsor, Abbott)
• Investigators: Study Director: Dawn Carlson, AbbVie

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.
• Smolen JS, van Vollenhoven RF, Florentinus S, Chen S, Suboticki JL, Kavanaugh A. Predictors of disease activity and structural progression after treatment with adalimumab plus methotrexate or continued methotrexate monotherapy in patients with early rheumatoid arthritis and suboptimal response to methotrexate. Ann Rheum Dis. 2018 Nov;77(11):1566-1572. doi: 10.1136/annrheumdis-2018-213502. Epub 2018 Aug 3.
• 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.
• Keystone EC, Breedveld FC, Kupper H, Li Y, Florentinus S, Sainsbury I. Long-term use of adalimumab as monotherapy after attainment of low disease activity with adalimumab plus methotrexate in patients with rheumatoid arthritis. RMD Open. 2018 Jun 13;4(1):e000637. doi: 10.1136/rmdopen-2017-000637. eCollection 2018.
• Moller B, Everts-Graber J, Florentinus S, Li Y, Kupper H, Finckh A. Low Hemoglobin and Radiographic Damage Progression in Early Rheumatoid Arthritis: Secondary Analysis From a Phase III Trial. Arthritis Care Res (Hoboken). 2018 Jun;70(6):861-868. doi: 10.1002/acr.23427. Epub 2018 Apr 25.
• Landewe R, Smolen JS, Florentinus S, Chen S, Guerette B, van der Heijde D. Existing joint erosions increase the risk of joint space narrowing independently of clinical synovitis in patients with early rheumatoid arthritis. Arthritis Res Ther. 2015 May 21;17(1):133. doi: 10.1186/s13075-015-0626-1.
• 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.
• Keystone EC, Haraoui B, Guerette B, Mozaffarian N, Liu S, Kavanaugh A. Clinical, functional, and radiographic implications of time to treatment response in patients with early rheumatoid arthritis: a posthoc analysis of the PREMIER study. J Rheumatol. 2014 Feb;41(2):235-43. doi: 10.3899/jrheum.121468. Epub 2013 Dec 1.
• Keystone EC, Breedveld FC, van der Heijde D, Landewe R, Florentinus S, Arulmani U, Liu S, Kupper H, Kavanaugh A. Longterm effect of delaying combination therapy with tumor necrosis factor inhibitor in patients with aggressive early rheumatoid arthritis: 10-year efficacy and safety of adalimumab from the randomized controlled PREMIER trial with open-label extension. J Rheumatol. 2014 Jan;41(1):5-14. doi: 10.3899/jrheum.130543. Epub 2013 Nov 15.
• Smolen JS, van der Heijde DM, Keystone EC, van Vollenhoven RF, Goldring MB, Guerette B, Cifaldi MA, Chen N, Liu S, Landewe RB. Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate. Ann Rheum Dis. 2013 Jul;72(7):1156-62. doi: 10.1136/annrheumdis-2012-201620. Epub 2012 Aug 22. Erratum In: Ann Rheum Dis. 2013 Aug;72(8):1432.
• Strand V, Rentz AM, Cifaldi MA, Chen N, Roy S, Revicki D. Health-related quality of life outcomes of adalimumab for patients with early rheumatoid arthritis: results from a randomized multicenter study. J Rheumatol. 2012 Jan;39(1):63-72. doi: 10.3899/jrheum.101161. Epub 2011 Nov 1.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2000
• Primary Completion (Actual): April 1, 2004
• Study Completion (Actual): April 1, 2012

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): July 12, 2013
• Last Update Submitted That Met QC Criteria: June 7, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Early Rheumatoid Arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Adalimumab; Methotrexate
• Other Study ID Numbers: DE013