Clinical trial NCT00420927: Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis
Official title: A Multicenter, Randomized, Double-Period, Double - Blind Study to Determine the Optimal Protocol for Treatment Initiation With Methotrexate and Adalimumab Combination Therapy in Patients With Early Rheumatoid Arthritis (OPTIMA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: Early Rheumatoid Arthritis
Tumor Necrosis Factor Optimization
Lead sponsor: Abbott
Sponsor class: INDUSTRY
First posted: 2007-01-11
Enrollment: 1032
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: This study compared the safety and efficacy of combination therapy with adalimumab plus methotrexate (MTX) to that of MTX monotherapy (i.e., placebo plus MTX) in subjects with early rheumatoid arthritis (RA).

Detailed description: This was a 78-week, multicenter, randomized, double-blind, double-treatment period study designed to compare the safety and efficacy of adalimumab and MTX with placebo and MTX in subjects with early RA. Subjects were randomized to receive adalimumab 40 mg every other week (eow) or placebo subcutaneous injections in combination with orally administered MTX for 26 weeks (Period 1). All subjects in all arms received open-label MTX weekly throughout the study (both Period 1 and Period 2).

At Weeks 22 and 26, subjects were assessed for achievement of low disease activity, defined as a DAS28 score below 3.2. DAS28 is a measure of RA disease activity calculated using the number of tender and swollen joints (out of a total of 28), C-reactive protein level (CRP, a blood marker of inflammation), and the patient's global assessment of disease activity (indicated by marking a 10 cm line between very good and very bad). Subjects who achieved low disease activity at Week 22 and 26 in the adalimumab arm at the end of Period 1 were randomized to receive MTX monotherapy (placebo and MTX) or combination therapy (adalimumab and MTX) in a 1:1 ratio for the duration of Period 2 (52 weeks, i.e., to Week 78 of the study). Subjects achieving low disease activity at Week 22 and 26 in the placebo arm (MTX monotherapy) at the end of Period 1 continued to receive MTX monotherapy (and placebo injections in a blinded fashion) for the duration of Period 2. Subjects failing to achieve low disease activity at Week 22 and 26 at the end of Period 1 received open-label combination therapy during Period 2 regardless of treatment assignment in Period 1.

Eligibility criteria: Inclusion Criteria

* Subject must be 18 or older and in good health
* Subject must meet the definition of early rheumatoid arthritis (RA) defined by the 1987-revised American College of Rheumatology (ACR) classification criteria and had disease duration of less than 1 year from diagnosis
* Subject must have a Disease Activity Score (DAS28, based on C-reactive protein) greater than 3.2, at least 6 swollen joints out of the 66 assessed, and at least 8 tender joints out of the 68 assessed
* Subject must fulfill at least one of the following three criteria:

  * Rheumatoid factor positive
  * Greater than 1 joint erosion
  * Anti-cyclic citrullinated peptide (CCP) antibody positive.

Exclusion Criteria

* Subject has previously received systemic anti-tumor necrosis factor (TNF) therapy
* Subject has received any biologic or investigational therapy within 6 weeks prior to Baseline
* Subject has been previously treated with more than 2 disease-modifying antirheumatic drugs (DMARDs) or MTX, had been treated with intra-articular or parenteral administration of corticosteroids in preceding 4 weeks, or had undergone joint surgery within the preceding 2 months at joints to be assessed during the study.

Primary outcomes:
measure: Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 4
timeFrame: Week 78
Secondary outcomes:
measure: Number of Subjects With Low Disease Activity (DAS28 Less Than 3.2) and No Radiographic Progression From Baseline (Change in mTSS Less Than or Equal to 0.5) at Week 78, Arm 2 vs. Arm 1
timeFrame: Week 78
measure: Number of Subjects With DAS28 Low Disease Activity (DAS28 Less Than 3.2) at Week 78
timeFrame: Week 78
measure: Number of Subjects With DAS28 Remission (DAS28 Less Than 2.6) at Week 78
timeFrame: Week 78
measure: Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS Less Than or Equal to 0.5) at Week 78
timeFrame: Week 78
measure: Number of Subjects Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 78
timeFrame: Week 78
measure: Number of Subjects Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 78
timeFrame: Week 78
measure: Number of Subjects Meeting American College of Rheumatology 70% (ACR70) Response Criteria at Week 78
timeFrame: Week 78
measure: Change From Baseline in DAS28 Score at Week 78
timeFrame: Baseline to Week 78
measure: Number of Subjects With Clinical Disease Activity Index (CDAI) Low Disease Activity (CDAI Less Than or Equal to 10) at Week 78
timeFrame: Week 78
measure: Number of Subjects With Simplified Disease Activity Index (SDAI) Low Disease Activity (SDAI Less Than or Equal to 11) at Week 78
timeFrame: Week 78
measure: Number of Subjects With Clinical Disease Activity Index (CDAI) Remission (CDAI Less Than or Equal to 2.8) at Week 78
timeFrame: Week 78
measure: Number of Subjects With Simplified Disease Activity Index (SDAI) Remission (SDAI Less Than or Equal to 3.3) at Week 78
timeFrame: Week 78
measure: Change From Baseline in CDAI Score at Week 78
timeFrame: Baseline to Week 78
measure: Change From Baseline in SDAI Score at Week 78
timeFrame: Baseline to Week 78
measure: Change From Baseline in Synovitis Score According to the Rheumatoid Arthritis Magnetic Resonance Imaging (RA MRI) Scoring System (RAMRIS) at Week 78
timeFrame: Baseline to Week 78
measure: Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5) and Normal Function (HAQ-DI Less Than 0.5) at Week 78
timeFrame: Week 78
measure: Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than or Equal to 0.5), and ACR70 Response at Week 78
timeFrame: Week 78
measure: Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS of Less Than or Equal to 0.5), Normal Function (HAQ-DI Less Than 0.5), and DAS28 Remission (DAS28 Less Than 2.6) at Week 78
timeFrame: Week 78
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site Reference ID/Investigator# 4560
state: Alabama
city: Birmingham
country: United States
facility: Site Reference ID/Investigator# 4547
state: Alabama
city: Huntsville
country: United States
facility: Site Reference ID/Investigator# 6222
state: Alabama
city: Mobile
country: United States
facility: Site Reference ID/Investigator# 4537
state: Alabama
city: Tuscaloosa
country: United States
facility: Site Reference ID/Investigator# 6758
state: Alabama
city: Hemet
country: United States
facility: Site Reference ID/Investigator# 9323
state: California
city: La Jolla
country: United States
facility: Site Reference ID/Investigator# 4568
state: California
city: Palm Desert
country: United States
facility: Site Reference ID/Investigator# 4535
state: California
city: Santa Monica
country: United States
facility: Site Reference ID/Investigator# 4571
state: California
city: Torrance
country: United States
facility: Site Reference ID/Investigator# 9271
state: California
city: Victorville
country: United States
facility: Site Reference ID/Investigator# 10746
state: California
city: Denver
country: United States
facility: Site Reference ID/Investigator# 4559
state: Colorado
city: Aventura
country: United States
facility: Site Reference ID/Investigator# 6229
state: Florida
city: Lake Mary
country: United States
facility: Site Reference ID/Investigator# 10603
state: Florida
city: Orange Park
country: United States
facility: Site Reference ID/Investigator# 9325
state: Florida
city: Palm Harbor
country: United States
facility: Site Reference ID/Investigator# 4550
state: Florida
city: Sarasota
country: United States
facility: Site Reference ID/Investigator# 4570
state: Florida
city: Tampa
country: United States
facility: Site Reference ID/Investigator# 4601
state: Florida
city: Vero Beach
country: United States
facility: Site Reference ID/Investigator# 4552
state: Florida
city: Meridian
country: United States
facility: Site Reference ID/Investigator# 10745
state: Idaho
city: Chicago
country: United States
facility: Site Reference ID/Investigator# 4548
state: Illinois
city: Springfield
country: United States
facility: Site Reference ID/Investigator# 4557
state: Illinois
city: Wichita
country: United States
facility: Site Reference ID/Investigator# 4605
state: Kansas
city: Wheaton
country: United States
facility: Site Reference ID/Investigator# 10741
state: Maryland
city: Fall River
country: United States
facility: Site Reference ID/Investigator# 6417
state: Massachusetts
city: Dover
country: United States
facility: Site Reference ID/Investigator# 4561
state: New Hampshire
city: Freehold
country: United States
facility: Site Reference ID/Investigator# 11222
state: New Jersey
city: Passaic
country: United States
facility: Site Reference ID/Investigator# 6228
state: New Jersey
city: Albuquerque
country: United States
facility: Site Reference ID/Investigator# 4544
state: New Mexico
city: Bronx
country: United States
facility: Site Reference ID/Investigator# 12821
state: New York
city: Orchard Park
country: United States
facility: Site Reference ID/Investigator# 4534
state: New York
city: Plainview
country: United States
facility: Site Reference ID/Investigator# 9324
state: New York
city: Smithtown
country: United States
facility: Site Reference ID/Investigator# 4600
state: New York
city: Mayfield Village
country: United States
facility: Site Reference ID/Investigator# 4549
state: Ohio
city: Bend
country: United States
facility: Site Reference ID/Investigator# 6227
state: Oregon
city: Duncansville
country: United States
facility: Site Reference ID/Investigator# 4546
state: Pennsylvania
city: West Reading
country: United States
facility: Site Reference ID/Investigator# 4564
state: Pennsylvania
city: Wexford
country: United States
facility: Site Reference ID/Investigator# 4558
state: Pennsylvania
city: Charleston
country: United States
facility: Site Reference ID/Investigator# 4533
state: South Carolina
city: Greenville
country: United States
facility: Site Reference ID/Investigator# 7482
state: South Carolina
city: Jackson
country: United States
facility: Site Reference ID/Investigator# 10743
state: Tennessee
city: Nashville
country: United States
facility: Site Reference ID/Investigator# 4562
state: Tennessee
city: Dallas
country: United States
facility: Site Reference ID/Investigator# 4536
state: Texas
city: Houston
country: United States
facility: Site Reference ID/Investigator# 4538
state: Texas
city: San Antonio
country: United States
facility: Site Reference ID/Investigator# 6899
state: Texas
city: Tyler
country: United States
facility: Site Reference ID/Investigator# 6381
state: Texas
city: Seattle
country: United States
facility: Site Reference ID/Investigator# 10744
state: Washington
city: Glendale
country: United States
facility: Site Reference ID/Investigator# 4545
state: Wisconsin
city: Oak Creek
country: United States
facility: Site Reference ID/Investigator# 4572
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Site Reference ID/Investigator# 3886
city: Buenos Aires
country: Argentina
facility: Site Reference ID/Investigator# 3888
city: Buenos Aires
country: Argentina
facility: Site Reference ID/Investigator# 6346
city: Quilmes
country: Argentina
facility: Site Reference ID/Investigator# 3887
city: San Miguel de Tucuman
country: Argentina
facility: Site Reference ID/Investigator# 3889
city: Campsie, Sydney
country: Australia
facility: Site Reference ID/Investigator# 8380
city: Clayton
country: Australia
facility: Site Reference ID/Investigator# 6954
city: Malvern East
country: Australia
facility: Site Reference ID/Investigator# 6940
city: Graz
country: Austria
facility: Site Reference ID/Investigator# 3915
city: Graz
country: Austria
facility: Site Reference ID/Investigator# 3911
city: Vienna
country: Austria
facility: Site Reference ID/Investigator# 3880
city: Vienna
country: Austria
facility: Site Reference ID/Investigator# 3885
city: Vienna
country: Austria
facility: Site Reference ID/Investigator# 3916
city: Vienna
country: Austria
facility: Site Reference ID/Investigator# 7792
city: Brussels
country: Belgium
facility: Site Reference ID/Investigator# 3914
city: Genk
country: Belgium
facility: Site Reference ID/Investigator# 3909
city: Gilly
country: Belgium
facility: Site Reference ID/Investigator# 3881
city: Liege
country: Belgium
facility: Site Reference ID/Investigator# 3376
city: Mechelen
country: Belgium
facility: Site Reference ID/Investigator# 6720
city: Sint-Niklaas
country: Belgium
facility: Site Reference ID/Investigator# 6718
city: Yvoir
country: Belgium
facility: Site Reference ID/Investigator# 3910
city: Burlington
country: Canada
facility: Site Reference ID/Investigator# 6701
city: Edmonton
country: Canada
facility: Site Reference ID/Investigator# 6834
city: Halifax
country: Canada
facility: Site Reference ID/Investigator# 7197
city: Hamilton
country: Canada
facility: Site Reference ID/Investigator# 3883
city: Hamilton
country: Canada
facility: Site Reference ID/Investigator# 3884
city: Montreal
country: Canada
facility: Site Reference ID/Investigator# 3907
city: Montreal
country: Canada
facility: Site Reference ID/Investigator# 3903
city: Ottawa
country: Canada
facility: Site Reference ID/Investigator# 5178
city: Richmond
country: Canada
facility: Site Reference ID/Investigator# 3904
city: Sainte-Foy, Quebec
country: Canada
facility: Site Reference ID/Investigator# 3912
city: Sarnia
country: Canada
facility: Site Reference ID/Investigator# 3901
city: St. John's
country: Canada
facility: Site Reference ID/Investigator# 3906
city: Toronto
country: Canada
facility: Site Reference ID/Investigator# 6542
city: Victoria
country: Canada
facility: Site Reference ID/Investigator# 3882
city: Windsor
country: Canada
facility: Site Reference ID/Investigator# 5616
city: Winnipeg
country: Canada
facility: Site Reference ID/Investigator# 5847
city: Winnipeg
country: Canada
facility: Site Reference ID/Investigator# 3905
city: Brno
country: Czech Republic
facility: Site Reference ID/Investigator# 3968
city: Hradec Kralove
country: Czech Republic
facility: Site Reference ID/Investigator# 3971
city: Ostrava
country: Czech Republic
facility: Site Reference ID/Investigator# 5559
city: Prague 2
country: Czech Republic
facility: Site Reference ID/Investigator# 3969
city: Uherske Hradiste
country: Czech Republic
facility: Site Reference ID/Investigator# 5548
city: Amiens
country: France
facility: Site Reference ID/Investigator# 3982
city: Le Mans
country: France
facility: Site Reference ID/Investigator# 3979
city: Paris Cedex 14
country: France
facility: Site Reference ID/Investigator# 3983
city: Strasbourg
country: France
facility: Site Reference ID/Investigator# 3918
city: Bad Nauheim
country: Germany
facility: Site Reference ID/Investigator# 3926
city: Berlin-Buch
country: Germany
facility: Site Reference ID/Investigator# 3928
city: Damp
country: Germany
facility: Site Reference ID/Investigator# 3978
city: Duesseldorf
country: Germany
facility: Site Reference ID/Investigator# 3924
city: Frankfurt/Main
country: Germany
facility: Site Reference ID/Investigator# 3927
city: Frankfurt
country: Germany
facility: Site Reference ID/Investigator# 3965
city: Freiburg
country: Germany
facility: Site Reference ID/Investigator# 3925
city: Halle
country: Germany
facility: Site Reference ID/Investigator# 4291
city: Hofheim
country: Germany
facility: Site Reference ID/Investigator# 8489
city: Munich
country: Germany
facility: Site Reference ID/Investigator# 3923
city: Osnabrueck
country: Germany
facility: Site Reference ID/Investigator# 8483
city: Ratingen
country: Germany
facility: Site Reference ID/Investigator# 8486
city: Vogelsang-Gommern
country: Germany
facility: Site Reference ID/Investigator# 3919
city: Zerbst
country: Germany
facility: Site Reference ID/Investigator# 6637
city: Budapest
country: Hungary
facility: Site Reference ID/Investigator# 3921
city: Budapest
country: Hungary
facility: Site Reference ID/Investigator# 3922
city: Debrecen
country: Hungary
facility: Site Reference ID/Investigator# 3920
city: Aguascallentes
country: Mexico
facility: Site Reference ID/Investigator# 3824
city: Leon, Guanajuato
country: Mexico
facility: Site Reference ID/Investigator# 3822
city: Mexico City
country: Mexico
facility: Site Reference ID/Investigator# 3825
city: Mexico City
country: Mexico
facility: Site Reference ID/Investigator# 3951
city: Mexico City
country: Mexico
facility: Site Reference ID/Investigator# 3890
city: Mexico City
country: Mexico
facility: Site Reference ID/Investigator# 3823
city: Mexico City
country: Mexico
facility: Site Reference ID/Investigator# 3891
city: Arnem
country: Netherlands
facility: Site Reference ID/Investigator# 3947
city: Hilversum
country: Netherlands
facility: Site Reference ID/Investigator# 3948
city: Auckland 6
country: New Zealand
facility: Site Reference ID/Investigator# 8485
city: Hamilton
country: New Zealand
facility: Site Reference ID/Investigator# 8488
city: Timaru
country: New Zealand
facility: Site Reference ID/Investigator# 8496
city: Wellington
country: New Zealand
facility: Site Reference ID/Investigator# 8511
city: Alesund
country: Norway
facility: Site Reference ID/Investigator# 7607
city: Kristiansand S
country: Norway
facility: Site Reference ID/Investigator# 7935
city: Levanger
country: Norway
facility: Site Reference ID/Investigator# 7506
city: Lillehammer
country: Norway
facility: Site Reference ID/Investigator# 7511
city: Trondheim
country: Norway
facility: Site Reference ID/Investigator# 7500
city: Bydgoszcz
country: Poland
facility: Site Reference ID/Investigator# 3963
city: Katowice
country: Poland
facility: Site Reference ID/Investigator# 3962
city: Lublin
country: Poland
facility: Site Reference ID/Investigator# 5560
city: Wroclaw
country: Poland
facility: Site Reference ID/Investigator# 3961
city: Caguas
country: Puerto Rico
facility: Site Reference ID/Investigator# 3944
city: Ponce
country: Puerto Rico
facility: Site Reference ID/Investigator# 3937
city: San Juan
country: Puerto Rico
facility: Site Reference ID/Investigator# 3934
city: San Juan
country: Puerto Rico
facility: Site Reference ID/Investigator# 3935
city: Piestany
country: Slovakia
facility: Site Reference ID/Investigator# 3959
city: Piestany
country: Slovakia
facility: Site Reference ID/Investigator# 3960
city: Berea, Durban
country: South Africa
facility: Site Reference ID/Investigator# 7177
city: Cape Town
country: South Africa
facility: Site Reference ID/Investigator# 7175
city: Cape Town
country: South Africa
facility: Site Reference ID/Investigator# 7178
city: Port Elizabeth
country: South Africa
facility: Site Reference ID/Investigator# 7176
city: Pretoria
country: South Africa
facility: Site Reference ID/Investigator# 7172
city: Soweto
country: South Africa
facility: Site Reference ID/Investigator# 7174
city: A Coruna
country: Spain
facility: Site Reference ID/Investigator# 3955
city: Bilbao
country: Spain
facility: Site Reference ID/Investigator# 13661
city: Elche (Alicante)
country: Spain
facility: Site Reference ID/Investigator# 3930
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 8524
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 3956
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 3943
city: Madrid
country: Spain
facility: Site Reference ID/Investigator# 3931
city: Oviedo
country: Spain
facility: Site Reference ID/Investigator# 3957
city: Santiago de Compostela
country: Spain
facility: Site Reference ID/Investigator# 3954
city: Zaragoza
country: Spain
facility: Site Reference ID/Investigator# 3932
city: Eskilstuna
country: Sweden
facility: Site Reference ID/Investigator# 4015
city: Falun
country: Sweden
facility: Site Reference ID/Investigator# 3984
city: Malmoe
country: Sweden
facility: Site Reference ID/Investigator# 4016
city: Stockholm
country: Sweden
facility: Site Reference ID/Investigator# 4014
city: Uppsala
country: Sweden
facility: Site Reference ID/Investigator# 4017
city: Bath
country: United Kingdom
facility: Site Reference ID/Investigator# 4012
city: Huddersfield
country: United Kingdom
facility: Site Reference ID/Investigator# 8495
city: Leeds
country: United Kingdom
facility: Site Reference ID/Investigator# 4048
city: London
country: United Kingdom
facility: Site Reference ID/Investigator# 4013
city: Newcastle upon Tyne
country: United Kingdom
facility: Site Reference ID/Investigator# 4046
city: Oxford
country: United Kingdom
facility: Site Reference ID/Investigator# 4047
city: Southampton
country: United Kingdom
facility: Site Reference ID/Investigator# 3985
city: York
country: United Kingdom
facility: Site Reference ID/Investigator# 7977
Study officials:
affiliation: Abbott
name: Laura Redden, MD, PhD
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: Kavanaugh A, van Vollenhoven RF, Fleischmann R, Emery P, Sainsbury I, Florentinus S, Chen S, Guerette B, Kupper H, Smolen JS. Testing treat-to-target outcomes with initial methotrexate monotherapy compared with initial tumour necrosis factor inhibitor (adalimumab) plus methotrexate in early rheumatoid arthritis. Ann Rheum Dis. 2018 Feb;77(2):289-292. doi: 10.1136/annrheumdis-2017-211871. Epub 2017 Nov 16.
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: 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: Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, Guerette B, Kupper H, Redden L, Arora V, Kavanaugh A. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet. 2014 Jan 25;383(9914):321-32. doi: 10.1016/S0140-6736(13)61751-1. Epub 2013 Oct 26.