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

Early Rheumatoid Arthritis Clinical Trial

— PREMIER  

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00195663
• Other study ID #: DE013
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2005
• Last updated: June 7, 2013
• Start date: December 2000
• Est. completion date: April 2012

Study information

• Verified date: June 2013
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Human Research Ethics CommitteeAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsCanada: Health CanadaCzech Republic: State Institute for Drug ControlDenmark: Danish Medicines AgencyFinland: Finnish Medicines AgencyFrance: Afssaps - Agence francaise de securite sanitaire des produits de sante (Saint-Denis)Germany: Paul-Ehrlich-InstitutIreland: Irish Medicines BoardItaly: National Monitoring Centre for Clinical Trials - Ministry of HealthItaly: Ethics CommitteeNorway: Norwegian Medicines AgencySlovakia: State Institute for Drug ControlSpain: Agencia Española de Medicamentos y Productos SanitariosSweden: Medical Products AgencySwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 799
• Est. completion date: April 2012
• Est. primary completion date: April 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Early Rheumatoid Arthritis

Intervention

Biological:
• Adalimumab

Drug:
• Methotrexate

Biological:
• Adalimumab placebo

Drug:
• Methotrexate placebo

Locations

Country	Name	City	State
Australia	Site Reference ID/Investigator# 310	Brisbane
Australia	Site Reference ID/Investigator# 755	Camperdown
Australia	Site Reference ID/Investigator# 337	Clayton
Australia	Site Reference ID/Investigator# 331	Darlinghurst, Sydney
Australia	Site Reference ID/Investigator# 745	Kogarah
Australia	Site Reference ID/Investigator# 738	Maroochydore
Australia	Site Reference ID/Investigator# 335	New Lambton
Australia	Site Reference ID/Investigator# 737	Shenton Park
Australia	Site Reference ID/Investigator# 307	South Hobart
Australia	Site Reference ID/Investigator# 427	West Heidelberg
Australia	Site Reference ID/Investigator# 739	Woodville
Austria	Site Reference ID/Investigator# 344	Vienna
Belgium	Site Reference ID/Investigator# 308	Brussels
Belgium	Site Reference ID/Investigator# 752	Brussels
Belgium	Site Reference ID/Investigator# 753	Brussels
Belgium	Site Reference ID/Investigator# 748	Diepenbeek
Belgium	Site Reference ID/Investigator# 6136	Ghent
Belgium	Site Ref # / Investigator 98256	Leuven
Belgium	Site Reference ID/Investigator# 333	Liege
Canada	Site Reference ID/Investigator# 4646	Edmonton
Canada	Site Reference ID/Investigator# 303	Hamilton
Canada	Site Reference ID/Investigator# 330	Hamilton
Canada	Site Reference ID/Investigator# 311	Montreal
Canada	Site Reference ID/Investigator# 4634	Montreal
Canada	Site Reference ID/Investigator# 309	Newmarket
Canada	Site Ref # / Investigator 98199	North York	Ontario
Canada	Site Reference ID/Investigator# 304	Pointe-Claire
Canada	Site Reference ID/Investigator# 4633	Richmond
Canada	Site Reference ID/Investigator# 763	St. John's
Canada	Site Reference ID/Investigator# 4635	Toronto
Canada	Site Reference ID/Investigator# 490	Toronto
Canada	Site Reference ID/Investigator# 760	Victoria
Canada	Site Reference ID/Investigator# 4632	Winnipeg
Czech Republic	Site Reference ID/Investigator# 754	Hradec Kralove
Czech Republic	Site Reference ID/Investigator# 332	Plzen
Czech Republic	Site Reference ID/Investigator# 734	Prague 2
Denmark	Site Ref # / Investigator 95878	Grasten
Finland	Site Reference ID/Investigator# 6135	Heinola
Finland	Site Ref # / Investigator 6134	Helsinki
France	Site Reference ID/Investigator# 428	Bobigny
France	Site Reference ID/Investigator# 348	Montpellier Cedex 5
France	Site Reference ID/Investigator# 4650	Paris Cedex 14
France	Site Reference ID/Investigator# 3415	Pierre Benite
France	Site Reference ID/Investigator# 733	Rennes
France	Site Reference ID/Investigator# 346	Strasbourg, Cedex 1
Germany	Site Reference ID/Investigator# 4631	Berlin
Germany	Site Reference ID/Investigator# 759	Berlin
Germany	Site Reference ID/Investigator# 3417	Berlin-Buch
Germany	Site Reference ID/Investigator# 4630	Erlangen
Germany	Site Reference ID/Investigator# 347	Freiburg
Germany	Site Reference ID/Investigator# 742	Goerlitz
Germany	Site Reference ID/Investigator# 746	Leipzig
Germany	Site Ref # / Investigator 98125	Munich
Germany	Site Reference ID/Investigator# 339	Munich
Germany	Site Reference ID/Investigator# 744	Ratingen
Germany	Site Reference ID/Investigator# 338	Vogelsang-Gommern
Ireland	Site Reference ID/Investigator# 740	Cork
Ireland	Site Reference ID/Investigator# 751	Dublin 4
Italy	Site Ref # / Investigator 95719	Genoa
Italy	Site Reference ID/Investigator# 323	Naples
Italy	Site Reference ID/Investigator# 345	Udine
Italy	Site Reference ID/Investigator# 756	Verona
Netherlands	Site Reference ID/Investigator# 343	Groningen
Netherlands	Site Reference ID/Investigator# 6133	Leiden
Netherlands	Site Reference ID/Investigator# 317	Maastricht
Netherlands	Site Reference ID/Investigator# 315	Nijmegen
Norway	Site Ref # / Investigator 95800	Osla
Norway	Site Ref # / Investigator 95875	Osla
Slovakia	Site Reference ID/Investigator# 3426	Piestany
Spain	Site Ref # / Investigator 96121	Alicante
Spain	Site Reference ID/Investigator# 735	Alicante
Spain	Site Reference ID/Investigator# 1525	Barcelona
Spain	Site Reference ID/Investigator# 1528	Barcelona
Spain	Site Reference ID/Investigator# 750	Guadalajara
Spain	Site Reference ID/Investigator# 1526	Madrid
Spain	Site Reference ID/Investigator# 741	Madrid
Spain	Site Reference ID/Investigator# 390	Santiago de Compostela
Spain	Site Reference ID/Investigator# 749	Sevilla
Sweden	Site Reference ID/Investigator# 2565	Stockholm
Sweden	Site Reference ID/Investigator# 4638	Stockholm
Sweden	Site Reference ID/Investigator# 728	Stockholm
Sweden	Site Ref # / Investigator 96126	Umea
Sweden	Site Reference ID/Investigator# 747	Uppsala
Sweden	Site Ref # / Investigator 96120	Vasteras
Sweden	Site Reference ID/Investigator# 736	Vasteras
Switzerland	Site Reference ID/Investigator# 334	Lausanne
United Kingdom	Site Ref # / Investigator 96116	Bangor
United Kingdom	Site Ref # / Investigator 95877	Cambridge
United Kingdom	Site Ref # / Investigator 98258	Hereford
United Kingdom	Site Ref # / Investigator 95795	Leeds
United Kingdom	Site Ref # / Investigator 95958	London
United Kingdom	Site Ref # / Investigator 98255	Newcastle upon Tyne
United States	Site Ref # / Investigator 96122	Austin	Texas
United States	Site Reference ID/Investigator# 306	Austin	Texas
United States	Site Reference ID/Investigator# 313	Austin	Texas
United States	Site Reference ID/Investigator# 762	Aventura	Florida
United States	Site Reference ID/Investigator# 316	Bethlehem	Pennsylvania
United States	Site Reference ID/Investigator# 318	Concord	New Hampshire
United States	Site Reference ID/Investigator# 319	Cumberland	Maryland
United States	Site Reference ID/Investigator# 2437	Dallas	Texas
United States	Site Reference ID/Investigator# 314	Dayton	Ohio
United States	Site Reference ID/Investigator# 2500	Denver	Colorado
United States	Site Reference ID/Investigator# 4649	Duncansville	Pennsylvania
United States	Site Reference ID/Investigator# 488	Durham	North Carolina
United States	Site Reference ID/Investigator# 757	Eugene	Oregon
United States	Site Ref # / Investigator 95960	Hagerstown	Maryland
United States	Site Reference ID/Investigator# 2532	Houston	Texas
United States	Site Reference ID/Investigator# 758	Houston	Texas
United States	Site Ref # / Investigator 95957	La Jolla	California
United States	Site Reference ID/Investigator# 429	La Jolla	California
United States	Site Reference ID/Investigator# 361	Lake Oswego	Oregon
United States	Site Reference ID/Investigator# 336	Lincoln	Nebraska
United States	Site Reference ID/Investigator# 2491	Los Angeles	California
United States	Site Reference ID/Investigator# 761	Oklahoma City	Oklahoma
United States	Site Reference ID/Investigator# 302	Rockford	Illinois
United States	Site Reference ID/Investigator# 328	Sarasota	Florida
United States	Site Reference ID/Investigator# 322	Scottsdale	Arizona
United States	Site Reference ID/Investigator# 321	Spokane	Washington
United States	Site Reference ID/Investigator# 327	Tampa	Florida
United States	Site Reference ID/Investigator# 326	Wheaton	Maryland
United States	Site Reference ID/Investigator# 2533	Worcester	Massachusetts
United States	Site Reference ID/Investigator# 305	Yakima	Washington
United States	Site Reference ID/Investigator# 325	Zephyrhills	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie (prior sponsor, Abbott)

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czech Republic,  Denmark,  Finland,  France,  Germany,  Ireland,  Italy,  Netherlands,  Norway,  Slovakia,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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.	No
Secondary	Composite Score of ACR50 Plus No Change in Modified Total Sharp Score		Year 10	No
Secondary	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	No
Secondary	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.	No

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