A Study to Evaluate Rituximab in Combination With Methotrexate in Methotrexate-Naive Patients With Active Rheumatoid Arthritis (IMAGE)

This study has been completed.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00299104
First received: March 2, 2006
Last updated: August 20, 2013
Last verified: August 2013
  Purpose

This is a phase III, randomized, controlled, double-blind, parallel group, international study in approximately 750 patients with active Rheumatoid Arthritis (RA) who are naive to Methotrexate (MTX) therapy. Rheumatoid Factor (RF)-positive and RF-negative patients will be enrolled and will be allocated equally between 3 treatment arms.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: folate
Drug: methotrexate
Drug: methylprednisolone
Drug: placebo
Drug: rituximab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Phase 3, Controlled, Double-Blind, Parallel-Group, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate (MTX) Compared to MTX Alone, in Methotrexate-Naive Patients With Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 [ Time Frame: Baseline and week 52 ] [ Designated as safety issue: No ]
    Rate of progression in structural joint damage (PJD) by change in Total Modified Sharp Score (TMSS) from screening to Week 52 in the modified intent-to-treat (MITT) population. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.


Secondary Outcome Measures:
  • Change From Baseline in Modified Sharp Erosion Score at Week 52 [ Time Frame: Baseline and week 52 ] [ Designated as safety issue: No ]
    Rate of progression in structural joint damage (PJD) by change in modified Sharp erosion score from screening to Week 52. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions.

  • Percentage of Patients Without Radiographic Progression at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    Percentage of patients without radiographic progression at Week 52, defined as change in total modified Sharp score (TMSS) <= 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.

  • Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    No radiographic progression is defined as a change in the total erosion score at Week 52 of less than or equal to zero.

  • Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 [ Time Frame: Baseline and week 52 ] [ Designated as safety issue: No ]
    Rate of progression in structural joint damage (PJD) by change in modified joint space narrowing (JSN) from screening to Week 52. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.

  • Change From Baseline in the Modified Total Sharp Score at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.

  • Change From Baseline in the Total Erosion Score at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The Total Erosion Score at Week 24 - Total Erosion Score at baseline is calculated.

  • Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    Joint Space Narrowing is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing.

  • Percentage of Participants Without Radiographic Progression at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    Percentage of patients without radiographic progression at Week 24 defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.

  • Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 [ Time Frame: Week 52 ] [ Designated as safety issue: No ]

    To achieve an ACR50 response requires at least a 50% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 50% improvement in three of five additional measurements from:

    • the physician's global assessment of disease activity
    • patient's global assessment of disease activity
    • patient's assessment of pain
    • HAQ-DI (Health Assessment Questionnaire disability index)
    • an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)

  • Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    DAS28-ESR is calculated from the following formula:

    (0.56 * TJC) + (0.28 * SJC) + (0.70 * ln ESR) + (0.014 * GH) TJC = tender joint count, based on 28 joints SJC = swollen joint count, based on 28 joints ESR = erythrocyte sedimentation rate in mm/h GH = patient's global assessment of disease activity A DAS28-ESR score of 5.1 or above is considered to indicate high disease activity. Patients can also be defined as having low disease activity (DAS28-ESR ≤ 3.2) or remission (DAS28-ESR < 2.6).


  • Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    To achieve an ACR70 response requires at least a 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in three of five additional measurements from:

    • the physician's global assessment of disease activity
    • patient's global assessment of disease activity
    • patient's assessment of pain
    • HAQ-DI (Health Assessment Questionnaire disability index)
    • an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)

  • Percentage of Participants With DAS28-ESR Remission at Week 52 [ Time Frame: Week 52 ] [ Designated as safety issue: No ]

    The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10.

    Remission is defined as achieving a DAS28-ESR score of less than 2.6


  • Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    European League Against Rheumatism (EULAR) criteria reflects an improvement in disease activity and an attainment of a lower degree of disease activity. A good response is defined as an improvement in the DAS28-ESR of > 1.2 compared with baseline, and attainment of a DAS28-ESR of < 3.2.

  • The Percentage of Participants With Major Clinical Response at Week 52 [ Time Frame: Week 52 ] [ Designated as safety issue: No ]

    Major clinical response is defined as a continuous six-month period of success by the ACR70.

    ACR70= 70% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 70% improvement in 3 of five additional measurements from:

    • the physician's global assessment of disease activity
    • patient's global assessment of disease activity
    • patient's assessment of pain
    • HAQ-DI (Health Assessment Questionnaire disability index)
    • an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)

  • Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 [ Time Frame: Week 52 ] [ Designated as safety issue: No ]

    The DAS28-4(ESR) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity (mm), and ESR. DAS28-4(ESR) scores range from 0 - 10.

    Low disease activity is defined as achieving a DAS28-ESR score of less than or equal to 3.2


  • Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    To achieve an ACR20 response requires at least a 20% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 20% improvement in three of five additional measurements from:

    • the physician's global assessment of disease activity
    • patient's global assessment of disease activity
    • patient's assessment of pain
    • HAQ-DI (Health Assessment Questionnaire disability index)
    • an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)

  • Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    To achieve an ACR90 response requires at least a 90% improvement compared with baseline in both Total Joint Count and Swollen Joint Count, as well as a 90% improvement in three of five additional measurements from:

    • the physician's global assessment of disease activity
    • patient's global assessment of disease activity
    • patient's assessment of pain
    • HAQ-DI (Health Assessment Questionnaire disability index)
    • an acute phase reactant C-Reactive Protein (CRP). (If CRP was missing then Erythrocyte Sedimentation Rate (ESR) was used if available.)

  • Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    FACIT-F is a 13-item questionnaire. Patients scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the patient's response to the questions (with the exception of 2 negatively stated), the greater the patient's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the patient's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). A higher score reflects an improvement in the patient's health status.

  • Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip,and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do).HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.

  • Change From Baseline in the SF-36 Physical Health Component Summary Score at Week 52 and Week 104 [ Time Frame: Baseline, Week 52, Week 104 ] [ Designated as safety issue: No ]

    The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.

    Means are adjusted for baseline value, Rheumatoid Factor status and region.


  • Change From Baseline in the SF-36 Mental Health Component Summary Score at Week 52 and Week 104 [ Time Frame: Baseline, Weeks 52, Week 104 ] [ Designated as safety issue: No ]

    The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.

    Means are adjusted for baseline value, Rheumatoid Factor status and region.


  • Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Each domain has at least two component questions. There are four possible responses for each component on a scale of 0 (without difficulty) to 3 (unable to do). Higher scores=greater dysfunction.

    Improved:HAQ-DI score change <=-0.22 Unchanged:HAQ-DI score change -0.22 to 0.22 Worsened:HAQ score => 0.22


  • Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Physical Health Component Score at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    MCID is defined as a change from baseline in SF-36 Physical Health Component Score of >5.42.

    SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.


  • Percentage of Patients With Minimally Clinically Important Difference (MCID) in the SF-36 Mental Health Component Score at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]

    MCID is defined as a change from baseline in SF-36 Mental Health Component Score of >6.33.

    SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical (PCS) and Mental (MCS) Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement.


  • Change From Baseline in the Modified Total Sharp Score at Week 104 [ Time Frame: Baseline, Week 104 ] [ Designated as safety issue: No ]
    The modified total sharp score is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change and higher scores represent a worsening of joint erosions and joint space narrowing.

  • Change From Baseline in the Total Erosion Score at Week 104 [ Time Frame: Baseline, Week 104 ] [ Designated as safety issue: No ]
    Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The change from the score at baseline to week 104 is calculated.

  • Percentage of Participants Without Radiographic Progression at Week 104 [ Time Frame: Baseline, Week 104 ] [ Designated as safety issue: No ]
    Percentage of patients without radiographic progression at Week 104, defined as change in total modified Sharp score (TMSS) ≤ 0. TMSS is the sum of the erosion score (ES) and the joint space narrowing (JSN) score and has a range of 0 to 398. The ES is the sum of joint scores collected for 46 joints and has a range of 0 to 230. The JSN is the sum of joint scores collected for 42 joints and has a range of 0 to 168. A score of 0 would indicate no change.

  • Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 [ Time Frame: Week 104 ] [ Designated as safety issue: No ]

    Total Erosion Score is determined by evaluation of fourteen sites in each wrist and hand and six joints in each foot using an eight-point scale from 0 (normal: no erosions) to 3.5 (Very severe; erosions of 100% of the articular surfaces. The score at baseline is compared to the score at week 104.

    No progression is defined as a change from score at screening to week 104 ≤0.


  • Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 [ Time Frame: Baseline, Week 104 ] [ Designated as safety issue: No ]
    The Stanford Health Assessment Questionnaire disability index (HAQ-DI) is a patient completed questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. Each domain has at least two component questions. There are four possible responses for each component ranging from 0(without any difficulty) to 4 (unable to do). HAQ-DI=sum of worst scores in each domain divided by the number of domains answered. A negative change from baseline indicates improvement.


Enrollment: 755
Study Start Date: January 2006
Study Completion Date: July 2013
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab (0.5 g x 2) + Methotrexate
Rituximab intravenously at a dose of 0.5 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6
Drug: folate
Intravenous repeating dose
Drug: methotrexate
Oral or parenteral repeating dose
Drug: methylprednisolone
Intravenous repeating dose
Drug: rituximab
Intravenous repeating dose
Experimental: Rituximab (1.0 g x 2) + Methotrexate
Rituximab intravenously at a dose of 1.0 g on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8. Subsequent Rituximab treatment courses were given at 24 week intervals for 5 years provided the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS-ESR) result was ≥2.6
Drug: folate
Intravenous repeating dose
Drug: methotrexate
Oral or parenteral repeating dose
Drug: methylprednisolone
Intravenous repeating dose
Drug: rituximab
Intravenous repeating dose
Placebo Comparator: Placebo + Methotrexate

Placebo intravenously on Days 1 and 15 + a background of methotrexate orally at a dose of 7.5 mg escalating by 2.5 mg a week every 1-2 weeks to achieve: 15 mg per week by Week 4 and 20 mg per week by Week 8.

From Week 104 participants were eligible to receive Rituximab 2 X 0.5 g or Rituximab 2 X 1.0 g every 24 weeks.

Drug: folate
Intravenous repeating dose
Drug: methotrexate
Oral or parenteral repeating dose
Drug: methylprednisolone
Intravenous repeating dose
Drug: placebo
Intravenous repeating dose

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Adult patients 18-80 years of age
  • RA for ≥ 2 months;
  • Receiving outpatient treatment
  • Patients naive to, and considered to be candidates for, methotrexate treatment

Exclusion criteria:

  • Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA
  • Inflammatory joint disease other than RA, or other systemic autoimmune disorder
  • Diagnosis of juvenile rheumatoid arthritis, or RA before the age of 16
  • Surgery within 12 weeks of study
  • Previous treatment with any approved or investigational biologic agent for RA, an anti-alpha4-integrin antibody or co-stimulation modulator, or cell-depleting therapy
  • Concurrent treatment with any biologic agent or DMARD other than methotrexate
  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: NCT00299104

Sponsors and Collaborators
Genentech, Inc.
Hoffmann-La Roche
Investigators
Study Director: Arndt Schottelius, M.D. Genentech, Inc.
  More Information

Additional Information:
No publications provided by Genentech, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00299104     History of Changes
Other Study ID Numbers: U3373g, WA17047
Study First Received: March 2, 2006
Results First Received: November 16, 2009
Last Updated: August 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
Rituxan
MTX
RA
IMAGE
WA17047

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Rituximab
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Anti-Inflammatory Agents
Antiemetics
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Antirheumatic Agents
Autonomic Agents
Central Nervous System Agents
Dermatologic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 23, 2014