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

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00195702
• Other study ID #: DE019
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2005
• Last updated: August 23, 2011
• Start date: February 2000
• Est. completion date: August 2010

Study information

• Verified date: August 2011
• Source: Abbott
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The purpose of the study was to assess the safety, immunogenicity, and clinical efficacy of adalimumab compared with placebo (during double-blind phase) and to to evaluate the long-term safety and maintenance of efficacy following repeated administration of adalimumab (during open-label extension phase) in patients with persistently active rheumatoid arthritis who were receiving concurrent methotrexate therapy.

Description:

This was a 10-year study which had an initial 52-week, double-blind, placebo-controlled phase followed by an open-label extension phase up to 9 years in duration. Data were analyzed for the double-blind phase using all patients who were randomized and received at least one dose of study drug through Week 52 and for all patients who received at least one dose of adalimumab during the 10-year study (the Intent-to-Treat [ITT] population).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 619
• Est. completion date: August 2010
• Est. primary completion date: September 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age 18 or older and in good health (Investigator discretion) with a recent stable medical history

• Met American College of Rheumatology (ACR) criteria for diagnosis of active rheumatoid arthritis (RA) and had at both screening and baseline visits >=6 swollen joints and >=9 tender joints, despite a minimum of 3-months treatment with methotrexate (MTX). (Distal interphalangeal joints [DIPs] were not to be included in joint count for inclusion. The screening and baseline visits could be 3 to 28 days apart for patients not previously receiving disease-modifying anti-rheumatic drugs [DMARDs] other than MTX or 4 to 6 weeks for patients requiring a DMARD washout period.)

• Insufficient efficacy with MTX 12.5 to 25 mg per week (10 mg per week if MTX intolerant).

• If patient on a second-line treatment (DMARD) other than MTX, he/she had to discontinue it for at least 28 days before the baseline visit (the washout period).

• Treatment with oral folic acid 1-3 mg/day or, if appropriate, up to 10 mg leucovorin per week.

• Both rheumatoid factor positivity and a C-reactive protein value >=1 mg/dL, or at least one joint erosion on X-ray.

Exclusion Criteria:

• Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study.

• Female subject who was pregnant or breast-feeding or considering becoming pregnant.

• Preceding treatment with any tumor necrosis factor (TNF) antagonist, including adalimumab.

• Prior exposure to alkylating agents, such as chlorambucil or cyclophosphamide.

• Intra-articular, intramuscular, or intravenous administration of corticosteroids within 4 weeks prior to the screening visit.

• Subject was wheelchair bound or bedridden.

Study 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
• Rheumatoid Arthritis

Intervention

Biological:
• Adalimumab
Self-administered, subcutaneous injection of 20 mg adalimumab (1.6 mL/injection) once weekly (ew) for up to 52 weeks.
• Adalimumab
Self-administered, subcutaneous injection of 40 mg adalimumab (1.6 mL/injection) every other week (eow) for up to 52 weeks.

Drug:
• Placebo
Self-administered, subcutaneous injection of placebo (1.6 mL/injection) once weekly (ew) for up to 52 weeks.

Biological:
• Adalimumab
Self-administration, subcutaneous (SC) injection of adalimumab 20 mg (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.
• Adalimumab
Self-administration, subcutaneous (SC) injection of adalimumab 40 mg (1.6 mL/injection) every other week (eow) (with a placebo 1.6 mL/injection on alternate weeks) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL injection) eow for up to Week 520.
• Adalimumab
Self-administration, subcutaneous (SC) injection of placebo solution (1.6 mL/injection) once weekly (ew) for 52 weeks, followed by self-administration, SC injection of adalimumab 40 mg (0.8 mL/injection) every other week (eow) for up to Week 520.

Locations

Country	Name	City	State
Canada	Site Ref # / Investigator 475	Calgary	Alberta
Canada	Site Ref # / Investigator 496	Halifax	Nova Scotia
Canada	Site Ref # / Investigator 363	Montreal	Quebec
Canada	Site Ref # / Investigator 444	Newmarket	Ontario
Canada	Site Ref # / Investigator 495	Penticton	British Columbia
Canada	Site Ref # / Investigator 2496	Richmond	British Columbia
Canada	Site Ref # / Investigator 60702	Saskatoon	Saskatchewan
Canada	Site Ref # / Investigator 2497	Toronto	Ontario
Canada	Site Ref # / Investigator 421	Toronto	Ontario
Canada	Site Ref # / Investigator 478	Toronto	Ontario
Canada	Site Ref # / Investigator 2495	Winnipeg	Manitoba
United States	Site Ref # / Investigator 60736	Anaheim	California
United States	Site Ref # / Investigator 716	Austin	Texas
United States	Site Ref # / Investigator 710	Aventura	Florida
United States	Site Ref # / Investigator 392	Baltimore	Maryland
United States	Site Ref # / Investigator 2436	Boise	Idaho
United States	Site Ref # / Investigator 465	Burlington	Massachusetts
United States	Site Ref # / Investigator 718	Charleston	South Carolina
United States	Site Ref # / Investigator 60732	Chicago	Illinois
United States	Site Ref # / Investigator 60735	Colmar	Pennsylvania
United States	Site Ref # / Investigator 353	Concord	New Hampshire
United States	Site Ref # / Investigator 354	Cumberland	Maryland
United States	Site Ref # / Investigator 712	Danbury	Connecticut
United States	Site Ref # / Investigator 364	Dover	New Hampshire
United States	Site Ref # / Investigator 2507	Duncansville	Pennsylvania
United States	Site Ref # / Investigator 498	Dunedin	Florida
United States	Site Ref # / Investigator 512	Durham	North Carolina
United States	Site Ref # / Investigator 717	East Norriton	Pennsylvania
United States	Site Ref # / Investigator 360	Escondido	California
United States	Site Ref # / Investigator 422	Eugene	Oregon
United States	Site Ref # / Investigator 60725	Falls Church	Virginia
United States	Site Ref # / Investigator 60728	Galveston	Texas
United States	Site Ref # / Investigator 471	Grand Rapids	Michigan
United States	Site Ref # / Investigator 340	Greensboro	North Carolina
United States	Site Ref # / Investigator 2509	Houston	Texas
United States	Site Ref # / Investigator 510	Houston	Texas
United States	Site Ref # / Investigator 424	Huntsville	Alabama
United States	Site Ref # / Investigator 485	Idaho Falls	Idaho
United States	Site Ref # / Investigator 2506	Indianapolis	Indiana
United States	Site Ref # / Investigator 473	Kalamazoo	Michigan
United States	Site Ref # / Investigator 731	Kansas City	Missouri
United States	Site Ref # / Investigator 60738	Kenosha	Wisconsin
United States	Site Ref # / Investigator 469	La Jolla	California
United States	Site Ref # / Investigator 714	La Jolla	California
United States	Site Ref # / Investigator 491	Lexington	Kentucky
United States	Site Ref # / Investigator 456	Mayfield Village	Ohio
United States	Site Ref # / Investigator 352	Mechanicsburg	Pennsylvania
United States	Site Ref # / Investigator 460	Memphis	Tennessee
United States	Site Ref # / Investigator 60726	Mercerville	New Jersey
United States	Site Ref # / Investigator 2510	Mobile	Alabama
United States	Site Ref # / Investigator 462	Nashville	Tennessee
United States	Site Ref # / Investigator 60723	Oklahoma	Oklahoma
United States	Site Ref # / Investigator 470	Oklahoma City	Oklahoma
United States	Site Ref # / Investigator 487	Omaha	Nebraska
United States	Site Ref # / Investigator 499	Orlando	Florida
United States	Site Ref # / Investigator 419	Palm Desert	California
United States	Site Ref # / Investigator 60729	Phoenix	Arizona
United States	Site Ref # / Investigator 2508	Portland	Maine
United States	Site Ref # / Investigator 461	Raleigh	North Carolina
United States	Site Ref # / Investigator 500	Raleigh	North Carolina
United States	Site Ref # / Investigator 60731	Raleigh	North Carolina
United States	Site Ref # / Investigator 711	Richmond	Virginia
United States	Site Ref # / Investigator 483	Rochester	New York
United States	Site Ref # / Investigator 60737	Salisbury	North Carolina
United States	Site Ref # / Investigator 492	San Jose	California
United States	Site Ref # / Investigator 60734	San Louis Obispo	California
United States	Site Ref # / Investigator 725	Scottsdale	Arizona
United States	Site Ref # / Investigator 509	Seattle	Washington
United States	Site Ref # / Investigator 60730	Shawnee Mission	Kansas
United States	Site Ref # / Investigator 732	South Bend	Indiana
United States	Site Ref # / Investigator 356	Spokane	Washington
United States	Site Ref # / Investigator 726	Springfield	Illinois
United States	Site Ref # / Investigator 371	St. Louis	Missouri
United States	Site Ref # / Investigator 482	St. Louis	Missouri
United States	Site Ref # / Investigator 502	St. Louis	Missouri
United States	Site Ref # / Investigator 464	Tacoma	Washington
United States	Site Ref # / Investigator 729	Tampa	Florida
United States	Site Ref # / Investigator 60739	Van Nuys	California
United States	Site Ref # / Investigator 358	Voorhees	New Jersey
United States	Site Ref # / Investigator 480	Wexford	Pennsylvania
United States	Site Ref # / Investigator 730	Wheaton	Maryland
United States	Site Ref # / Investigator 467	Wichita	Kansas
United States	Site Ref # / Investigator 494	Wichita	Kansas
United States	Site Ref # / Investigator 2512	Worcester	Massachusetts
United States	Site Ref # / Investigator 2511	Wyomissing	Pennsylvania
United States	Site Ref # / Investigator 60724	Wyomissing	Pennsylvania
United States	Site Ref # / Investigator 463	Zephyrhills	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Abbott

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 24	Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Week 24	No
Primary	Change From Baseline in Modified Total Sharp X-ray Score at Week 52	Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 52. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease.	Baseline and Week 52	No
Primary	Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 52	Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement.	Baseline and Week 52	No
Secondary	Number of Participants Meeting ACR20 Response Criteria at Week 52	Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Week 52	No
Secondary	Change From Baseline in Modified Total Sharp X-ray Score at Week 24	Modified total Sharp x-ray score (mTSS) is a measure of change in joint health. Radiographs of hands/wrists and feet were obtained at screening and Week 24. Digitized images of these were scored in a blinded manner. Joints were scored for erosions from 0 (no damage) to 5 and for joint space narrowing from 0 (no damage) to 4; scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). Large positive change indicates disease progression; small positive/no change indicates slowing/halting of disease progression; and negative change may indicate improvement of disease.	Baseline and Week 24	No
Secondary	Change From Baseline in the Disability Index of the Health Assessment Questionnaire (HAQ) at Week 24	Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Negative mean changes from baseline in the disability index of the HAQ indicated improvement.	Baseline and Week 24	No
Secondary	Maintenance of the Disability Index of the HAQ at Week 52 for Participants Who Were Responders at Week 12 or Week 24	Subjects assessed their ability to perform the following tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) maintain hygiene; and 8) maintain daily activity. Subjects assessed their ability to do these tasks over the past week by marking their response on a questionnaire. Possible responses/scores included the following: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Responders had a >= 0.22-unit decrease (improvement) in HAQ scores from baseline to Week 12 or 24.	Week 52	No
Secondary	Maintenance of ACR20 Response at Week 52 for Participants Who Were ACR20 Responders at Week 24	Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Week 52	No
Secondary	Number of Participants With a Continuous ACR70 Response for 6 Months During 52 Weeks of Treatment	Patients were responders if they had: >= 70% improvement in tender joint count; >= 70% improvement in swollen joint count; and >= 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Baseline through Week 52	No
Secondary	Time to First Response According to ACR20 Criteria - Number of Participants Meeting ACR20 Criteria for the First Time at Each Time Point	Patients were responders if they had: >= 20% improvement in tender joint count; >= 20% improvement in swollen joint count; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Baseline through Week 52	No
Secondary	Time to First Response According to ACR50 Criteria - Number of Participants Meeting ACR50 Criteria for the First Time at Each Time Point	Patients were responders if they had: >= 50% improvement in tender joint count; >= 50% improvement in swollen joint count; and >= 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Baseline through Week 52	No
Secondary	Time to First Response According to ACR70 Criteria - Number of Participants Meeting ACR70 Criteria for the First Time at Each Time Point	Patients were responders if they had: >= 70% improvement in tender joint count; >= 70% improvement in swollen joint count; and >= 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant: C-reactive protein. Patients withdrawing early or receiving additional disease-modifying anti-rheumatic drugs (DMARDs) after Week 16 were non-responders.	Baseline through Week 52	No
Secondary	Estimated Yearly Progression of Rheumatoid Arthritis	Estimated yearly progression was defined as modified total Sharp x-ray score at baseline divided by duration of rheumatoid arthritis disease at baseline. Actual progression during the study was defined as modified total Sharp x-ray score at Week 52 minus modified total Sharp x-ray score at baseline divided by the duration of the study. The range of scores for the modified total Sharp x-ray score was 0 (normal) to 398 (maximal disease).	Baseline and Week 52	No