Study to Determine the Effects of Different Doses of Methotrexate (MTX) When Taken With Adalimumab in Subjects With Early Rheumatoid Arthritis (RA)

Early Rheumatoid Arthritis Clinical Trial

— CONCERTO  

Official title:

A Double-Blind, Randomized, Parallel-Arm, Multicenter Study to Determine the Dose Response of Methotrexate (MTX) in Combination Therapy With Adalimumab in Subjects With Early Rheumatoid Arthritis (CONCERTO)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01185301
• Other study ID #: M12-073
• Secondary ID: 2010-019514-24
• Status: Completed
• Phase: Phase 3
• First received: August 18, 2010
• Last updated: September 11, 2013
• Start date: October 2010
• Est. completion date: September 2012

Study information

• Verified date: September 2013
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationGermany: Paul-Ehrlich-InstitutCzech Republic: State Institute for Drug ControlPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsCanada: Health CanadaArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsSpain: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the effects of different doses of methotrexate (MTX) when taken with adalimumab in subjects with early rheumatoid arthritis (RA).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 395
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female subjects at least 18 years of age

• Subject has a diagnosis of Rheumatoid Arthritis (RA) as defined by either the 1987-revised American College of Rheumatology (ACR) classification criteria or the new ACR/ European League Against Rheumatism (EULAR) diagnostic criteria for RA 2010 and has a disease duration of less than 1 year from diagnosis by a licensed health care provider

• Subject must meet the following criteria:

1. Disease Activity Score of C-reactive Protein (DAS28[CRP]) = 3.2 (at the Baseline visit only)

2. At least 6 swollen joints out of 66 assessed (at the Screening and Baseline visits)

3. At least 8 tender joints out of 68 assessed (at the Screening and Baseline visits)

4. C-reactive protein (CRP) = 1.5 mg/dL (at the Screening visit only), or erythrocyte sedimentation rate (ESR) = 28 mm/1h (at the Screening and Baseline visits)

5. Fulfill at least one of the following three criteria: Rheumatoid Factor (RF) positive, have at least 1 bony erosion, anti-cyclic citrullinated peptide (anti-CCP) antibody positive

• Subject is judged to be in good health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), and a 12-lead electrocardiogram (ECG) performed during Screening

Exclusion Criteria:

• Subject has previous exposure to any systemic biologic therapy including adalimumab

• Subject has been previously treated with greater than 1 disease modifying antirheumatic drugs (DMARDs) or with methotrexate (MTX)

• Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study)

• Subject has chronic arthritis diagnosed before age 17 years

• History of invasive infection (e.g., listeriosis and histoplasmosis), chronic or active Hepatitis C infection, human immunodeficiency virus (HIV) infection, immunodeficiency syndrome, chronic recurring infections or active tuberculosis (TB)

• Hepatitis B virus: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the hepatitis B virus DNA (HBV DNA) polymerase chain reaction (PCR) qualitative test

• Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the Baseline visit

• Female subject who is pregnant or breast-feeding or considering becoming pregnant

Study Design

Allocation: Randomized, Endpoint Classification: 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
Pre-filled syringe every other week

Drug:
• methotrexate
weekly oral capsule dosing

Locations

Country	Name	City	State
Argentina	Site Reference ID/Investigator# 44924	Buenos Aires
Argentina	Site Reference ID/Investigator# 44926	Buenos Aires
Argentina	Site Reference ID/Investigator# 44925	Rosario, Santa Fe
Argentina	Site Reference ID/Investigator# 47302	San Juan
Austria	Site Reference ID/Investigator# 44928	Graz
Austria	Site Reference ID/Investigator# 44927	Vienna
Austria	Site Reference ID/Investigator# 44930	Vienna
Belgium	Site Reference ID/Investigator# 44934	Brussels
Belgium	Site Reference ID/Investigator# 44935	Genk
Belgium	Site Reference ID/Investigator# 44933	Gilly
Belgium	Site Reference ID/Investigator# 44932	Liege
Canada	Site Reference ID/Investigator# 43783	Edmonton
Canada	Site Reference ID/Investigator# 43782	Winnipeg
Czech Republic	Site Reference ID/Investigator# 44937	Brno
Czech Republic	Site Reference ID/Investigator# 48962	Ceske Budejovice
Czech Republic	Site Reference ID/Investigator# 44939	Ostrava
Czech Republic	Site Reference ID/Investigator# 44936	Prague 2
Czech Republic	Site Reference ID/Investigator# 44938	Uherske Hradiste
Czech Republic	Site Reference ID/Investigator# 48963	Zlin
Germany	Site Reference ID/Investigator# 44941	Berlin
Germany	Site Reference ID/Investigator# 44945	Berlin-Buch
Germany	Site Reference ID/Investigator# 44942	Munich
Germany	Site Reference ID/Investigator# 44944	Ratingen
Germany	Site Reference ID/Investigator# 44943	Zerbst
Poland	Site Reference ID/Investigator# 44946	Bydgoszcz
Poland	Site Reference ID/Investigator# 44982	Lodz
Poland	Site Reference ID/Investigator# 46584	Torun
Poland	Site Reference ID/Investigator# 44983	Warsaw
Poland	Site Reference ID/Investigator# 44984	Warsaw
Puerto Rico	Site Reference ID/Investigator# 38975	Caguas
Puerto Rico	Site Reference ID/Investigator# 38916	San Juan
Puerto Rico	Site Reference ID/Investigator# 39693	San Juan
Puerto Rico	Site Reference ID/Investigator# 40122	San Juan
Puerto Rico	Site Reference ID/Investigator# 39692	Vega Baja
Spain	Site Reference ID/Investigator# 44947	A Coruna
Spain	Site Reference ID/Investigator# 44987	Elche (Alicante)
Spain	Site Reference ID/Investigator# 44948	Oviedo (Asturias)
Spain	Site Reference ID/Investigator# 47782	Valencia
United States	Site Reference ID/Investigator# 44284	Atlanta	Georgia
United States	Site Reference ID/Investigator# 41424	Bronx	New York
United States	Site Reference ID/Investigator# 38971	Charleston	South Carolina
United States	Site Reference ID/Investigator# 40651	Clifton	New Jersey
United States	Site Reference ID/Investigator# 42202	Columbus	Ohio
United States	Site Reference ID/Investigator# 39672	Covington	Louisiana
United States	Site Reference ID/Investigator# 39643	Dallas	Texas
United States	Site Reference ID/Investigator# 45325	Dallas	Texas
United States	Site Reference ID/Investigator# 41423	Duncansville	Pennsylvania
United States	Site Reference ID/Investigator# 41422	Freehold	New Jersey
United States	Site Reference ID/Investigator# 38907	Gainesville	Georgia
United States	Site Reference ID/Investigator# 40463	Greenville	North Carolina
United States	Site Reference ID/Investigator# 38912	Hemet	California
United States	Site Reference ID/Investigator# 52042	Houston	Texas
United States	Site Reference ID/Investigator# 38973	Huntsville	Alabama
United States	Site Reference ID/Investigator# 39666	Jackson	Tennessee
United States	Site Reference ID/Investigator# 38909	Jacksonville	Florida
United States	Site Reference ID/Investigator# 38972	Lawrenceville	Georgia
United States	Site Reference ID/Investigator# 45323	Little Rock	Arkansas
United States	Site Reference ID/Investigator# 41962	Mesa	Arizona
United States	Site Reference ID/Investigator# 40422	Miami	Florida
United States	Site Reference ID/Investigator# 44282	Norman	Oklahoma
United States	Site Reference ID/Investigator# 42204	Omaha	Nebraska
United States	Site Reference ID/Investigator# 39260	Phoenix	Arizona
United States	Site Reference ID/Investigator# 39670	Rock Island	Illinois
United States	Site Reference ID/Investigator# 38910	Sarasota	Florida
United States	Site Reference ID/Investigator# 40602	Seattle	Washington
United States	Site Reference ID/Investigator# 42282	Springfield	Illinois
United States	Site Reference ID/Investigator# 39673	Victorville	California
United States	Site Reference ID/Investigator# 38911	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
AbbVie (prior sponsor, Abbott)

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Canada,  Czech Republic,  Germany,  Poland,  Puerto Rico,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With 28-Joint Disease Activity Score of C-reactive Protein (DAS28[CRP]) Low Disease Activity at Week 26	Percentage of participants achieving low disease activity as defined by a clinical response (DAS28[CRP] < 3.2). 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 are 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 26	No
Secondary	Percentage of Participants With DAS28(CRP) Remission at Week 26	Disease remission was defined as a disease activity score, based on CRP, for 28 joints that was < 2.6 (DAS28[CRP] < 2.6). 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 are included in the DAS28 score. Scores on the DAS28 range from 0 to 10.	Week 26	No
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 20 Criteria Response at Week 26	Response, as defined by ACR 20 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are 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: Physician global assessment of disease activity; Patient global assessment of disease activity; Patient assessment of pain; Disability Index of the Health Assessment Questionnaire; Acute phase reactant value (C-reactive protein).	Baseline, Week 26	No
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 50 Criteria Response at Week 26	Response, as defined by ACR 50 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are 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: Physician global assessment of disease activity; Patient global assessment of disease activity; Patient assessment of pain; Disability Index of the Health Assessment Questionnaire; Acute phase reactant value (C-reactive protein).	Baseline, Week 26	No
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 70 Criteria Response at Week 26	Response, as defined by ACR 70 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are 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: Physician global assessment of disease activity; Patient global assessment of disease activity; Patient assessment of pain; Disability Index of the Health Assessment Questionnaire; Acute phase reactant value (C-reactive protein).	Baseline, Week 26	No
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 90 Criteria Response at Week 26	Response, as defined by ACR 90 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are met: = 90% improvement in tender joint count; = 90% improvement in swollen joint count; and = 90% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity; Patient global assessment of disease activity; Patient assessment of pain; Disability Index of the Health Assessment Questionnaire; Acute phase reactant value (C-reactive protein).	Baseline, Week 26	No
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 100 Criteria Response at Week 26	Response, as defined by ACR 100 criteria at Week 26. A participant is a responder if the following 3 criteria for improvement from Baseline are met: = 100% improvement in tender joint count; = 100% improvement in swollen joint count; and = 100% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity; Patient global assessment of disease activity; Patient assessment of pain; Disability Index of the Health Assessment Questionnaire; Acute phase reactant value (C-reactive protein).	Baseline, Week 26	No
Secondary	Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score at Week 26	The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 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 0 represents no disability and 3 very severe, high-dependency disability. HAQ remission indicating normal physical function is defined by HAQ-DI score of < 0.5. Negative change from Baseline in the overall score indicates improvement.	Baseline, Week 26	No
Secondary	Percentage of Participants With a Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) = -0.22 at Week 26	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. The minimal clinically important difference (MCID) defined for the HAQ-DI is a change from Baseline of = 0.22. HAQ remission indicating normal physical function is defined by HAQ-DI score of < 0.5. Negative change from Baseline in the overall score indicates improvement.	Baseline, Week 26	No
Secondary	Change From Baseline in Modified Total Sharp Score (mTSS) at Week 26	The modified Total Sharp Score (mTSS) is a measure of change in joint health from digitized images of radiographs of hands and feet. 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, Week 26	No
Secondary	Percentage of Participants With No Radiographic Progression at Week 26	"No radiographic progression" was defined as a change from Baseline in modified Total Sharp Score (mTSS) at Week 26 of = 0.5. mTSS is a measure of change in joint health from digitized images of radiographs of hands and feet. 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, Week 26	No
Secondary	Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission at Week 26	SDAI is a measure of disease activity derived as follows: SDAI = SJC28 + TJC28 + GH (cm) + PhGA (cm) + CRP (mg/dL), where TJC28 and SJC28 represent total tender joint count and total swollen joint count, respectively, based on 28 joints (including the left and right side of the body), GH = Patient's Global Assessment of Disease Activity, and PhGA = Physician's Global Assessment of Disease Activity (both measured on a visual analogue scale with a range of 0 [none] to 10 [severe]), and CRP is C-reactive protein measured in mg/dL. SDAI total score = 0 to 86. SDAI = 3.3 indicates disease remission, > 3.4 to 11 = low disease activity, > 11 to 26 = moderate disease activity, and > 26 = high disease activity.	Week 26	No
Secondary	Percentage of Participants With Clinical Disease Activity Index (CDAI) Remission at Week 26	CDAI is a measure of disease activity derived as follows: CDAI = SJC28 + TJC28 + GH (cm) + PhGA (cm) where TJC28 and SJC28 represent total tender joint count and total swollen joint count, respectively, based on 28 joints (including the left and right side of the body), GH = Patient's Global Assessment of Disease Activity, and PhGA = Physician's Global Assessment of Disease Activity (both measured on a visual analogue scale with a range of 0 [none] to 10 [severe]). CDAI total score = 0 to 76. CDAI = 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity.	Week 26	No

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