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

NCT00195663 | Completed Phase 3 Results

• 1 other identifier: DE013
• Study Type: interventional
• Target: 799
• Locations: 18 countries
• Sites: 122

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.

Conditions

Early Rheumatoid Arthritis

Keywords

Early Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (32)

• Change From Baseline in the Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52

  Baseline and Week 52

• Number of Participants Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 104

  Baseline and Week 104

• Change From Baseline in Modified Total Sharp Score (mTSS) at Week 104

  Baseline and Week 104

• Number of Participants Who Achieved Clinical Remission, Defined as a Disease Activity 28 (DAS28) Score < 2.6 at Week 52

  Week 52

• Change From Baseline in the Physical Component of the Short Form-36 Health Status Survey (SF-36) at Week 52

  Baseline and Week 52

Study Arms (3)

Adalimumab

EXPERIMENTAL

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; Drug: Methotrexate placebo

Adalimumab + methotrexate

EXPERIMENTAL

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; Drug: Methotrexate

Methotrexate

EXPERIMENTAL

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

Interventions

Adalimumab BIOLOGICAL

Also known as: ABT-D2E7, Humira

Adalimumab; Adalimumab + methotrexate

Methotrexate DRUG

Adalimumab + methotrexate; Methotrexate

Adalimumab placebo BIOLOGICAL

Methotrexate

Methotrexate placebo DRUG

Adalimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• AbbVie (prior sponsor, Abbott): lead

Study Sites (123)

Site Reference ID/Investigator# 322

Scottsdale, Arizona, 85260, United States

Location

Site Ref # / Investigator 95957

La Jolla, California, 92037, United States

Location

Site Reference ID/Investigator# 429

La Jolla, California, 92037, United States

Location

Site Reference ID/Investigator# 2491

Los Angeles, California, 90048, United States

Location

Site Reference ID/Investigator# 2500

Denver, Colorado, 80230, United States

Location

Site Reference ID/Investigator# 762

Aventura, Florida, 33180, United States

Location

Site Reference ID/Investigator# 328

Sarasota, Florida, 34239, United States

Location

Site Reference ID/Investigator# 327

Tampa, Florida, 33614, United States

Location

Site Reference ID/Investigator# 325

Zephyrhills, Florida, 33542, United States

Location

Site Reference ID/Investigator# 302

Rockford, Illinois, 61103, United States

Location

Site Reference ID/Investigator# 319

Cumberland, Maryland, 21502, United States

Location

Site Ref # / Investigator 95960

Hagerstown, Maryland, 21740, United States

Location

Site Reference ID/Investigator# 326

Wheaton, Maryland, 20902, United States

Location

Site Reference ID/Investigator# 2533

Worcester, Massachusetts, 01605-0000, United States

Location

Site Reference ID/Investigator# 336

Lincoln, Nebraska, 68516, United States

Location

Site Reference ID/Investigator# 318

Concord, New Hampshire, 03301, United States

Location

Site Reference ID/Investigator# 488

Durham, North Carolina, 27704, United States

Location

Site Reference ID/Investigator# 314

Dayton, Ohio, 45408, United States

Location

Site Reference ID/Investigator# 761

Oklahoma City, Oklahoma, 73103, United States

Location

Site Reference ID/Investigator# 757

Eugene, Oregon, 97401, United States

Location

Site Reference ID/Investigator# 361

Lake Oswego, Oregon, 97035, United States

Location

Site Reference ID/Investigator# 316

Bethlehem, Pennsylvania, 18015, United States

Location

Site Reference ID/Investigator# 4649

Duncansville, Pennsylvania, 16635, United States

Location

Site Ref # / Investigator 96122

Austin, Texas, 78705, United States

Location

Site Reference ID/Investigator# 306

Austin, Texas, 78705, United States

Location

Site Reference ID/Investigator# 313

Austin, Texas, 78705, United States

Location

Site Reference ID/Investigator# 2437

Dallas, Texas, 75231, United States

Location

Site Reference ID/Investigator# 2532

Houston, Texas, 77074, United States

Location

Site Reference ID/Investigator# 758

Houston, Texas, 77074, United States

Location

Site Reference ID/Investigator# 321

Spokane, Washington, 99204, United States

Location

Site Reference ID/Investigator# 305

Yakima, Washington, 98902, United States

Location

Site Reference ID/Investigator# 310

Brisbane, 4102, Australia

Location

Site Reference ID/Investigator# 755

Camperdown, 2050, Australia

Location

Site Reference ID/Investigator# 337

Clayton, 3168, Australia

Location

Site Reference ID/Investigator# 331

Darlinghurst, Sydney, 2010, Australia

Location

Site Reference ID/Investigator# 745

Kogarah, 2217, Australia

Location

Site Reference ID/Investigator# 738

Maroochydore, 4558, Australia

Location

Site Reference ID/Investigator# 335

New Lambton, 2305, Australia

Location

Site Reference ID/Investigator# 737

Shenton Park, 6008, Australia

Location

Site Reference ID/Investigator# 307

South Hobart, 7004, Australia

Location

Site Reference ID/Investigator# 427

West Heidelberg, 3081, Australia

Location

Site Reference ID/Investigator# 739

Woodville, 5011, Australia

Location

Site Reference ID/Investigator# 344

Vienna, 1090, Austria

Location

Site Reference ID/Investigator# 753

Brussels, 1070, Belgium

Location

Site Reference ID/Investigator# 308

Brussels, 1090, Belgium

Location

Site Reference ID/Investigator# 752

Brussels, 1200, Belgium

Location

Site Reference ID/Investigator# 748

Diepenbeek, 3590, Belgium

Location

Site Reference ID/Investigator# 6136

Ghent, 9000, Belgium

Location

Site Ref # / Investigator 98256

Leuven, 3000, Belgium

Location

Site Reference ID/Investigator# 333

Liège, 4000, Belgium

Location

Site Ref # / Investigator 98199

North York, Ontario, M3H 5Y8, Canada

Location

Site Reference ID/Investigator# 4646

Edmonton, T6G 2S2, Canada

Location

Site Reference ID/Investigator# 303

Hamilton, L8N 1Y2, Canada

Location

Site Reference ID/Investigator# 330

Hamilton, L8N 2B6, Canada

Location

Site Reference ID/Investigator# 4634

Montreal, H2L 1S6, Canada

Location

Site Reference ID/Investigator# 311

Montreal, H3Z 2Z3, Canada

Location

Site Reference ID/Investigator# 309

Newmarket, L3Y 3R7, Canada

Location

Site Reference ID/Investigator# 304

Pointe-Claire, H9J 3W3, Canada

Location

Site Reference ID/Investigator# 4633

Richmond, V7C 5L9, Canada

Location

Site Reference ID/Investigator# 763

St. John's, A1A 5E8, Canada

Location

Site Reference ID/Investigator# 4635

Toronto, M4N 3M5, Canada

Location

Site Reference ID/Investigator# 490

Toronto, M5L 3L9, Canada

Location

Site Reference ID/Investigator# 760

Victoria, V8V 3P9, Canada

Location

Site Reference ID/Investigator# 4632

Winnipeg, R3N OK6, Canada

Location

Site Reference ID/Investigator# 754

Hradec Králové, 500 05, Czechia

Location

Site Reference ID/Investigator# 332

Pilsen, 305 99, Czechia

Location

Site Reference ID/Investigator# 734

Prague, 128 50, Czechia

Location

Site Ref # / Investigator 95878

Gråsten, 6300, Denmark

Location

Site Reference ID/Investigator# 6135

Heinola, FI-18120, Finland

Location

Site Ref # / Investigator 6134

Helsinki, 00029, Finland

Location

Site Reference ID/Investigator# 428

Bobigny, 93009, France

Location

Site Reference ID/Investigator# 348

Montpellier, 34295, France

Location

Site Reference ID/Investigator# 4650

Paris, 75679, France

Location

Site Reference ID/Investigator# 3415

Pierre-Bénite, 69310, France

Location

Site Reference ID/Investigator# 733

Rennes, 35056, France

Location

Site Reference ID/Investigator# 346

Strasbourg, 67098, France

Location

Site Reference ID/Investigator# 4631

Berlin, 10117, Germany

Location

Site Reference ID/Investigator# 759

Berlin, 14059, Germany

Location

Site Reference ID/Investigator# 3417

Buch, 13125, Germany

Location

Site Reference ID/Investigator# 4630

Erlangen, 91054, Germany

Location

Site Reference ID/Investigator# 347

Freiburg im Breisgau, 79106, Germany

Location

Site Reference ID/Investigator# 742

Görlitz, 02826, Germany

Location

Site Reference ID/Investigator# 746

Leipzig, 04103, Germany

Location

Site Ref # / Investigator 98125

Munich, 80336, Germany

Location

Site Reference ID/Investigator# 339

Munich, 80336, Germany

Location

Site Reference ID/Investigator# 744

Ratingen, 40882, Germany

Location

Site Reference ID/Investigator# 338

Vogelsang-Gommern, 39245, Germany

Location

Site Reference ID/Investigator# 740

Cork, WDQ-23-KM9, Ireland

Location

Site Reference ID/Investigator# 751

Dublin, Ireland

Location

Site Ref # / Investigator 95719

Genoa, 16132, Italy

Location

Site Reference ID/Investigator# 323

Naples, 80131, Italy

Location

Site Reference ID/Investigator# 345

Udine, 33100, Italy

Location

Site Reference ID/Investigator# 756

Verona, 37134, Italy

Location

Site Reference ID/Investigator# 343

Groningen, 9713 GZ, Netherlands

Location

Site Reference ID/Investigator# 6133

Leiden, 2333 ZA, Netherlands

Location

Site Reference ID/Investigator# 317

Maastricht, 6229 HX, Netherlands

Location

Site Reference ID/Investigator# 315

Nijmegen, 6500 HB, Netherlands

Location

Site Ref # / Investigator 95800

Oslo, 0027, Norway

Location

Site Ref # / Investigator 95875

Oslo, 0370, Norway

Location

Site Reference ID/Investigator# 3426

Piešťany, 92112, Slovakia

Location

Site Ref # / Investigator 96121

Alicante, 03010, Spain

Location

Site Reference ID/Investigator# 735

Alicante, 03010, Spain

Location

Site Reference ID/Investigator# 1525

Barcelona, 08036, Spain

Location

Site Reference ID/Investigator# 1528

Barcelona, 08915, Spain

Location

Site Reference ID/Investigator# 750

Guadalajara, 19002, Spain

Location

Site Reference ID/Investigator# 1526

Madrid, 28040, Spain

Location

Site Reference ID/Investigator# 741

Madrid, 28040, Spain

Location

Site Reference ID/Investigator# 390

Santiago de Compostela, 15706, Spain

Location

Site Reference ID/Investigator# 749

Seville, 41014, Spain

Location

Site Reference ID/Investigator# 728

Stockholm, 113 24, Sweden

Location

Site Reference ID/Investigator# 2565

Stockholm, 171 76, Sweden

Location

Site Reference ID/Investigator# 4638

Stockholm, SE-141 86, Sweden

Location

Site Ref # / Investigator 96126

Umeå, 901 84, Sweden

Location

Site Reference ID/Investigator# 747

Uppsala, 75185, Sweden

Location

Site Ref # / Investigator 96120

Västerås, S-721 89, Sweden

Location

Site Reference ID/Investigator# 736

Västerås, S-721 89, Sweden

Location

Site Reference ID/Investigator# 334

Lausanne, 1011, Switzerland

Location

Site Ref # / Investigator 96116

Bangor, LL57 2PW, United Kingdom

Location

Site Ref # / Investigator 95877

Cambridge, CB2 0QQ, United Kingdom

Location

Site Ref # / Investigator 98258

Hereford, HR1 2ER, United Kingdom

Location

Site Ref # / Investigator 95795

Leeds, LS1 3EX, United Kingdom

Location

Site Ref # / Investigator 95958

London, SE1 9RT, United Kingdom

Location

Site Ref # / Investigator 98255

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (12)

• 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.

  PMID: 31707982 DERIVED

• 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.

  PMID: 30076156 DERIVED

• 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.

  PMID: 29955381 DERIVED

• 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.

  PMID: 29018564 DERIVED

• 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.

  PMID: 28950430 DERIVED

• 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.

  PMID: 27338778 DERIVED

• 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.

  PMID: 25994819 DERIVED

• 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.

  PMID: 25073879 DERIVED

• 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.

  PMID: 24293583 DERIVED

• 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.

  PMID: 24241487 DERIVED

• 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.

  PMID: 22915617 DERIVED

• 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.

  PMID: 22045836 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Adalimumab; Methotrexate

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Medical Services
• Organization: AbbVie (prior sponsor, Abbott)

800-633-9110

Study Officials

• Dawn Carlson

  AbbVie

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2005
• First Posted: September 20, 2005
• Study Start: December 1, 2000
• Primary Completion: April 1, 2004
• Study Completion: April 1, 2012
• Last Updated: July 12, 2013
• Results First Posted: February 25, 2010

Record last verified: 2013-06

Locations

ES (9); DE (11); NO (2); AU (11); GB (6); IT (4); SL (1); IE (2); FR (6); BE (7); DK (1); FI (2); CH (1); CA (14); SE (7); CZ (3); US (31); NL (4)