Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis (OPTIMA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Abbott
ClinicalTrials.gov Identifier:
NCT00420927
First received: January 9, 2007
Last updated: April 16, 2012
Last verified: April 2012
  Purpose

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).


Condition Intervention Phase
Rheumatoid Arthritis
Biological: adalimumab
Drug: methotrexate
Biological: placebo
Phase 4

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

Resource links provided by NLM:


Further study details as provided by Abbott:

Primary Outcome Measures:
  • 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 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.


Secondary Outcome Measures:
  • 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 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07, with scores below 3.2 indicating low disease activity. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.

  • Number of Subjects With DAS28 Low Disease Activity (DAS28 Less Than 3.2) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

  • Number of Subjects With DAS28 Remission (DAS28 Less Than 2.6) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

  • Number of Subjects With No Radiographic Progression (Change From Baseline in mTSS Less Than or Equal to 0.5) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448. 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.

  • Number of Subjects Meeting American College of Rheumatology 20% (ACR20) Response Criteria at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    Subjects were responders if they had greater than or equal to 20% improvement in tender joint count; greater than or equal to 20% improvement in swollen joint count; and greater than or equal to 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).

  • Number of Subjects Meeting American College of Rheumatology 50% (ACR50) Response Criteria at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    Subjects were responders if they had: greater than or equal to 50% improvement in tender joint count; greater than or equal to 50% improvement in swollen joint count; and greater than or equal to 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).

  • Number of Subjects Meeting American College of Rheumatology 70% (ACR70) Response Criteria at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    Subjects were responders if they had: greater than or equal to 70% improvement in tender joint count; greater than or equal to 70% improvement in swollen joint count; and greater than or equal to 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).

  • Change From Baseline in DAS28 Score at Week 78 [ Time Frame: Baseline to Week 78 ] [ Designated as safety issue: No ]
    The Disease Activity Score (DAS28) is calculated using the number of tender and swollen joints (out of 28 counted), C-reactive protein level, and the patient's global assessment of disease activity. The calculated range of DAS28 is 0.49 to 9.07. A DAS28 less than 2.6 indicates clinical remission, DAS28 2.6 to 3.2 indicates low disease activity, DAS28 3.2 to less than 5.1 indicates moderate disease activity, and DAS28 of 5.1 or greater indicates high disease activity.

  • Number of Subjects With Clinical Disease Activity Index (CDAI) Low Disease Activity (CDAI Less Than or Equal to 10) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

  • Number of Subjects With Simplified Disease Activity Index (SDAI) Low Disease Activity (SDAI Less Than or Equal to 11) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

  • Number of Subjects With Clinical Disease Activity Index (CDAI) Remission (CDAI Less Than or Equal to 2.8) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

  • Number of Subjects With Simplified Disease Activity Index (SDAI) Remission (SDAI Less Than or Equal to 3.3) at Week 78 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

  • Change From Baseline in CDAI Score at Week 78 [ Time Frame: Baseline to Week 78 ] [ Designated as safety issue: No ]
    The CDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, and physician's global assessment of disease activity. Scores range from 0 to 76.0, with a higher score reflecting worsening disease.

  • Change From Baseline in SDAI Score at Week 78 [ Time Frame: Baseline to Week 78 ] [ Designated as safety issue: No ]
    The SDAI is calculated using number of swollen joints (28 joints assessed), number of tender joints (28 joints assessed), patient's global assessment of disease activity, physician's global assessment of disease activity, and acute phase reactant (C-reactive protein). Scores range from 0.1 to 86.0, with a higher score reflecting worsening disease.

  • Change From Baseline in Synovitis Score According to the Rheumatoid Arthritis Magnetic Resonance Imaging (RA MRI) Scoring System (RAMRIS) at Week 78 [ Time Frame: Baseline to Week 78 ] [ Designated as safety issue: No ]
    Synovitis was assessed using high-field magnetic resonance imaging (MRI) of the hand and wrist. Images were read and scored according to the Outcomes Measures in Rheumatology Clinical Trials' Rheumatoid Arthritis MRI Scoring System (OMERACT RAMRIS). Synovitis in the wrist and finger joints in the most affected hand was scored from 0 (normal) to 3 (severe), for a maximum total score of 21.

  • 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 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    In the Health Assessment Questionnaire Disability Index (HAQ-DI), participants rated their ability to perform daily tasks on a scale of 0 (without any difficulty) to 3 (unable to do). A mean score of 0-1 represents mild to moderate functional disability, 1-2 represents moderate to severe, 2-3 severe to very severe disability. For the modified Total Sharp score (mTSS), x-rays of hand/wrist and feet joints are scored for erosions (0 to 5) and joint space narrowing (0 to 4). The erosion score and the narrowing score are added to determine the total score, which ranges from 0 (no damage) to 448.

  • 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 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (worst joint damage). American College of Rheumatology 70% (ACR70) response indicates at least 70% improvement in tender and swollen joint counts and 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; HAQ-DI; and C-reactive protein.

  • 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 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]
    In the Health Assessment Questionnaire Disability Index (HAQ-DI), a score of 0-1 represents mild to moderate, 1-2 moderate to severe, 2-3 severe to very severe disability. The modified Total Sharp score (mTSS) ranges from 0 (no joint damage) to 448 (severe joint damage). The Disease Activity Score (DAS28) ranges from 0.49 to 9.07, with scores less than 2.6 indicating clinical remission.


Enrollment: 1032
Study Start Date: December 2006
Study Completion Date: July 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ADA+MTX/PBO+MTX (Arm 1)
Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, MTX monotherapy plus blinded placebo (PBO) during Period 2
Biological: adalimumab
Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Other Names:
  • Humira
  • D2E7
Drug: methotrexate
Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Biological: placebo
Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Experimental: ADA+MTX/ADA+MTX (Arm2)
Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1 and Period 2
Biological: adalimumab
Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Other Names:
  • Humira
  • D2E7
Drug: methotrexate
Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Experimental: ADA+MTX/OL ADA+MTX (Arm 3)
Combination therapy with methotrexate (MTX) and blinded adalimumab (ADA) during Period 1, open-label combination therapy with ADA + MTX during Period 2
Biological: adalimumab
Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Other Names:
  • Humira
  • D2E7
Drug: methotrexate
Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Experimental: PBO+MTX/PBO+MTX (Arm 4)
Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1 and Period 2
Drug: methotrexate
Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Biological: placebo
Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Experimental: PBO+MTX/OL ADA+MTX (Arm 5)
Methotrexate (MTX) monotherapy plus blinded placebo (PBO) during Period 1, open-label combination therapy with adalimumab (ADA) and MTX during Period 2.
Biological: adalimumab
Adalimumab 40 mg/0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)
Other Names:
  • Humira
  • D2E7
Drug: methotrexate
Methotrexate 2.5 mg tablets administered orally once a week starting at 7.5 mg/week with dose escalation (weekly or every other week) by 2.5 mg intervals to 20 mg/week.
Biological: placebo
Placebo for adalimumab 0.8 mL prefilled syringe injected subcutaneously (SC) every other week (eow)

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00420927

  Show 170 Study Locations
Sponsors and Collaborators
Abbott
Investigators
Study Director: Laura Redden, MD, PhD Abbott
  More Information

No publications provided by Abbott

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Abbott
ClinicalTrials.gov Identifier: NCT00420927     History of Changes
Other Study ID Numbers: M06-810, 2006-004139-31
Study First Received: January 9, 2007
Results First Received: July 1, 2011
Last Updated: April 16, 2012
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria : Federal Ministry for Labour, Health, and Social Affairs
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada
Czech Republic: State Institute for Drug Control
France: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé
Germany: Federal Institute for Drugs and Medical Devices
Germany: Paul-Ehrlich-Institut
Hungary: National Institute of Pharmacy
Mexico: Federal Commission for Protection Against Health Risks
Netherlands: Ministry of Health, Welfare and Sport
New Zealand: Health Research Council
New Zealand: Ministry of Health
Norway: Norwegian Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Poland: Ministry of Health
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Institutional Review Board

Keywords provided by Abbott:
Early Rheumatoid Arthritis
Tumor Necrosis Factor Optimization

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Adalimumab
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on August 28, 2014