Clinical trial NCT00195663: Efficacy and Safety of Adalimumab and Methotrexate (MTX) Versus MTX Monotherapy in Subjects With Early Rheumatoid Arthritis
Official title: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Early Rheumatoid Arthritis
Keywords: Early Rheumatoid Arthritis
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2005-09-20
Enrollment: 799
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 52
timeFrame: Baseline and 52 Weeks
measure: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52
timeFrame: Baseline and Week 52
measure: Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104
timeFrame: Baseline and Week 104
measure: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104
timeFrame: Baseline and Week 104
measure: Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52
timeFrame: Week 52
measure: Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52
timeFrame: Baseline and Week 52
measure: Number of Participants With Major Clinical Response After 104 Weeks of Treatment
timeFrame: Any 6 continuous months from Baseline to Week 104
measure: Change From Baseline in the Mental Component of the Short Form-36 Health Status Survey (SF-36) at Week 52
timeFrame: Baseline and Week 52
measure: Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Weeks 26 and 76
timeFrame: Baseline and Weeks 26 and 76
measure: Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria During the Double-blind Phase
timeFrame: Baseline and Weeks 26, 52, 76, and 104
measure: Number of Participants Meeting American College of Rheumatology 70% (ACR70) Response Criteria During the Double-blind Phase
timeFrame: Baseline and Weeks 26, 52, 76, and 104
measure: Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 12, 26, 76, and 104
measure: Number of Participants With Improvement in the HAQ-DI Score ≥ 0.3 During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 26, 52, 76, and 104
measure: Change From Baseline in Health Utilities Index Mark 2 and Mark 3 (HUI 2/3) During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 26, 52, and 104
measure: Change From Baseline in the Short Form-36 Health Status Survey (SF-36) During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 26 and 104
measure: Numeric American College of Rheumatology (ACR-N) During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 26, 52, 76, and 104
measure: Change From Baseline in Disease Activity Score (DAS28) During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 26, 52, 76, and 104
measure: Change From Baseline in Joint Erosion Score During the Double-blind Treatment Period
timeFrame: Baseline and Weeks 52 and 104
measure: Change From Baseline in Joint Space Narrowing Score During the Double-blind Treatment Period
timeFrame: Baseline and Weeks 52 and 104
measure: Number of Participants With No Worsening in Modified Total Sharp Score or Components During the Double-blind Treatment Phase
timeFrame: Baseline and Weeks 52 and 104
measure: Number of Participants With No Erosions at Baseline and No New Erosions at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Number of Participants With Non-Involved Joints at Baseline and No Newly Involved Joints at Weeks 52 and 104
timeFrame: Baseline and Weeks 52 and 104
measure: Number of Participants Meeting ACR20 Response Criteria Over 10 Years by Adalimumab Exposure
timeFrame: Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
measure: Number of Participants Meeting ACR50 Response Criteria Over 10 Years by Adalimumab Exposure
timeFrame: Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
measure: Number of Participants Meeting ACR70 Response Criteria Over 10 Years by Adalimumab Exposure
timeFrame: Baseline and after 1, 2, 5, and 10 years of adalimumab exposure. Baseline was the last value prior to the first dose of adalimumab.
measure: Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) Over 10 Years by Adalimumab Exposure
timeFrame: 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.
measure: Change From Baseline in DAS28 Over 10 Years by Adalimumab Exposure
timeFrame: 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.
measure: Number of Participants With DAS28 < 2.6 and < 3.2 Over 10 Years by Adalimumab Exposure
timeFrame: After 1, 2, 5, and 10 years of adalimumab exposure
measure: Change From Baseline in Modified Total Sharp Score (mTSS) Over 10 Years
timeFrame: Baseline (prior to first study drug treatment) and Years 2 and 10
measure: Number of Participants With No Radiographic Progression Over 10 Years
timeFrame: Baseline (prior to first study drug treatment) and Years 2 and 10.
measure: Composite Score of ACR50 Plus No Change in Modified Total Sharp Score
timeFrame: Year 10
measure: Number of Participants With a Major Clinical Response Over 10 Years by Adalimumab Exposure
timeFrame: 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
measure: Number of Participants With Improvement in HAQ-DI by 0.22 and 0.5 Units Over 10 Years by Adalimumab Exposure
timeFrame: 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.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Site Reference ID/Investigator# 322
state: Arizona
city: La Jolla
country: United States
facility: Site Ref # / Investigator 95957
state: California
city: La Jolla
country: United States
facility: Site Reference ID/Investigator# 429
state: California
city: Los Angeles
country: United States
facility: Site Reference ID/Investigator# 2491
state: California
city: Denver
country: United States
facility: Site Reference ID/Investigator# 2500
state: Colorado
city: Aventura
country: United States
facility: Site Reference ID/Investigator# 762
state: Florida
city: Sarasota
country: United States
facility: Site Reference ID/Investigator# 328
state: Florida
city: Tampa
country: United States
facility: Site Reference ID/Investigator# 327
state: Florida
city: Zephyrhills
country: United States
facility: Site Reference ID/Investigator# 325
state: Florida
city: Rockford
country: United States
facility: Site Reference ID/Investigator# 302
state: Illinois
city: Cumberland
country: United States
facility: Site Reference ID/Investigator# 319
state: Maryland
city: Hagerstown
country: United States
facility: Site Ref # / Investigator 95960
state: Maryland
city: Wheaton
country: United States
facility: Site Reference ID/Investigator# 326
state: Maryland
city: Worcester
country: United States
facility: Site Reference ID/Investigator# 2533
state: Massachusetts
city: Lincoln
country: United States
facility: Site Reference ID/Investigator# 336
state: Nebraska
city: Concord
country: United States
facility: Site Reference ID/Investigator# 318
state: New Hampshire
city: Durham
country: United States
facility: Site Reference ID/Investigator# 488
state: North Carolina
city: Dayton
country: United States
facility: Site Reference ID/Investigator# 314
state: Ohio
city: Oklahoma City
country: United States
facility: Site Reference ID/Investigator# 761
state: Oklahoma
city: Eugene
country: United States
facility: Site Reference ID/Investigator# 757
state: Oregon
city: Lake Oswego
country: United States
facility: Site Reference ID/Investigator# 361
state: Oregon
city: Bethlehem
country: United States
facility: Site Reference ID/Investigator# 316
state: Pennsylvania
city: Duncansville
country: United States
facility: Site Reference ID/Investigator# 4649
state: Pennsylvania
city: Austin
country: United States
facility: Site Ref # / Investigator 96122
state: Texas
city: Austin
country: United States
facility: Site Reference ID/Investigator# 306
state: Texas
city: Austin
country: United States
facility: Site Reference ID/Investigator# 313
state: Texas
city: Dallas
country: United States
facility: Site Reference ID/Investigator# 2437
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 2532
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 758
state: Texas
city: Spokane
country: United States
facility: Site Reference ID/Investigator# 321
state: Washington
city: Yakima
country: United States
facility: Site Reference ID/Investigator# 305
state: Washington
city: Brisbane
country: Australia
facility: Site Reference ID/Investigator# 310
city: Camperdown
country: Australia
facility: Site Reference ID/Investigator# 755
city: Clayton
country: Australia
facility: Site Reference ID/Investigator# 337
city: Darlinghurst, Sydney
country: Australia
facility: Site Reference ID/Investigator# 331
city: Kogarah
country: Australia
facility: Site Reference ID/Investigator# 745
city: Maroochydore
country: Australia
facility: Site Reference ID/Investigator# 738
city: New Lambton
country: Australia
facility: Site Reference ID/Investigator# 335
city: Shenton Park
country: Australia
facility: Site Reference ID/Investigator# 737
city: South Hobart
country: Australia
facility: Site Reference ID/Investigator# 307
city: West Heidelberg
country: Australia
facility: Site Reference ID/Investigator# 427
city: Woodville
country: Australia
facility: Site Reference ID/Investigator# 739
city: Vienna
country: Austria
facility: Site Reference ID/Investigator# 344
city: Brussels
country: Belgium
facility: Site Reference ID/Investigator# 753
city: Brussels
country: Belgium
facility: Site Reference ID/Investigator# 308
city: Brussels
country: Belgium
facility: Site Reference ID/Investigator# 752
city: Diepenbeek
country: Belgium
facility: Site Reference ID/Investigator# 748
city: Ghent
country: Belgium
facility: Site Reference ID/Investigator# 6136
city: Leuven
country: Belgium
facility: Site Ref # / Investigator 98256
city: Liege
country: Belgium
facility: Site Reference ID/Investigator# 333
city: North York
country: Canada
facility: Site Ref # / Investigator 98199
state: Ontario
city: Edmonton
country: Canada
facility: Site Reference ID/Investigator# 4646
city: Hamilton
country: Canada
facility: Site Reference ID/Investigator# 303
city: Hamilton
country: Canada
facility: Site Reference ID/Investigator# 330
city: Montreal
country: Canada
facility: Site Reference ID/Investigator# 4634
city: Montreal
country: Canada
facility: Site Reference ID/Investigator# 311
city: Newmarket
country: Canada
facility: Site Reference ID/Investigator# 309
city: Pointe-Claire
country: Canada
facility: Site Reference ID/Investigator# 304
city: Richmond
country: Canada
facility: Site Reference ID/Investigator# 4633
city: St. John's
country: Canada
facility: Site Reference ID/Investigator# 763
city: Toronto
country: Canada
facility: Site Reference ID/Investigator# 4635
city: Toronto
country: Canada
facility: Site Reference ID/Investigator# 490
city: Victoria
country: Canada
facility: Site Reference ID/Investigator# 760
city: Winnipeg
country: Canada
facility: Site Reference ID/Investigator# 4632
city: Hradec Kralove
country: Czech Republic
facility: Site Reference ID/Investigator# 754
city: Plzen
country: Czech Republic
facility: Site Reference ID/Investigator# 332
city: Prague 2
country: Czech Republic
facility: Site Reference ID/Investigator# 734
city: Grasten
country: Denmark
facility: Site Ref # / Investigator 95878
city: Heinola
country: Finland
facility: Site Reference ID/Investigator# 6135
city: Helsinki
country: Finland
facility: Site Ref # / Investigator 6134
city: Bobigny
country: France
facility: Site Reference ID/Investigator# 428
city: Montpellier Cedex 5
country: France
facility: Site Reference ID/Investigator# 348
city: Paris Cedex 14
country: France
facility: Site Reference ID/Investigator# 4650
city: Pierre Benite
country: France
facility: Site Reference ID/Investigator# 3415
city: Rennes
country: France
facility: Site Reference ID/Investigator# 733
city: Strasbourg, Cedex 1
country: France
facility: Site Reference ID/Investigator# 346
city: Berlin-Buch
country: Germany
facility: Site Reference ID/Investigator# 3417
city: Berlin
country: Germany
facility: Site Reference ID/Investigator# 4631
city: Berlin
country: Germany
facility: Site Reference ID/Investigator# 759
city: Erlangen
country: Germany
facility: Site Reference ID/Investigator# 4630
city: Freiburg
country: Germany
facility: Site Reference ID/Investigator# 347
city: Goerlitz
country: Germany
facility: Site Reference ID/Investigator# 742
city: Leipzig
country: Germany
facility: Site Reference ID/Investigator# 746
city: Munich
country: Germany
facility: Site Ref # / Investigator 98125
city: Munich
country: Germany
facility: Site Reference ID/Investigator# 339
city: Ratingen
country: Germany
facility: Site Reference ID/Investigator# 744
city: Vogelsang-Gommern
country: Germany
facility: Site Reference ID/Investigator# 338
city: Cork
country: Ireland
facility: Site Reference ID/Investigator# 740
city: Dublin 4
country: Ireland
facility: Site Reference ID/Investigator# 751
city: Genoa
country: Italy
facility: Site Ref # / Investigator 95719
city: Naples
country: Italy
facility: Site Reference ID/Investigator# 323
city: Udine
country: Italy
facility: Site Reference ID/Investigator# 345
city: Verona
country: Italy
facility: Site Reference ID/Investigator# 756
city: Groningen
country: Netherlands
facility: Site Reference ID/Investigator# 343
city: Leiden
country: Netherlands
facility: Site Reference ID/Investigator# 6133
city: Maastricht
country: Netherlands
facility: Site Reference ID/Investigator# 317
city: Nijmegen
country: Netherlands
facility: Site Reference ID/Investigator# 315
city: Osla
country: Norway
facility: Site Ref # / Investigator 95800
city: Osla
country: Norway
facility: Site Ref # / Investigator 95875
city: Piestany
country: Slovakia
facility: Site Reference ID/Investigator# 3426
city: Alicante
country: Spain
facility: Site Ref # / Investigator 96121
city: Alicante
country: Spain
facility: Site Reference ID/Investigator# 735
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator# 1525
city: Barcelona
country: Spain
facility: Site Reference ID/Investigator# 1528
city: Guadalajara
country: Spain
facility: Site Reference ID/Investigator# 750
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 1526
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 741
city: Santiago de Compostela
country: Spain
facility: Site Reference ID/Investigator# 390
city: Sevilla
country: Spain
facility: Site Reference ID/Investigator# 749
city: Stockholm
country: Sweden
facility: Site Reference ID/Investigator# 728
city: Stockholm
country: Sweden
facility: Site Reference ID/Investigator# 2565
city: Stockholm
country: Sweden
facility: Site Reference ID/Investigator# 4638
city: Umea
country: Sweden
facility: Site Ref # / Investigator 96126
city: Uppsala
country: Sweden
facility: Site Reference ID/Investigator# 747
city: Vasteras
country: Sweden
facility: Site Ref # / Investigator 96120
city: Vasteras
country: Sweden
facility: Site Reference ID/Investigator# 736
city: Lausanne
country: Switzerland
facility: Site Reference ID/Investigator# 334
city: Bangor
country: United Kingdom
facility: Site Ref # / Investigator 96116
city: Cambridge
country: United Kingdom
facility: Site Ref # / Investigator 95877
city: Hereford
country: United Kingdom
facility: Site Ref # / Investigator 98258
city: Leeds
country: United Kingdom
facility: Site Ref # / Investigator 95795
city: London
country: United Kingdom
facility: Site Ref # / Investigator 95958
city: Newcastle upon Tyne
country: United Kingdom
facility: Site Ref # / Investigator 98255
Study officials:
affiliation: AbbVie
name: Dawn Carlson
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.