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

This study is ongoing, but not recruiting participants.

Sponsor:

Collaborator:

Hoffmann-La Roche

Information provided by (Responsible Party):

Genentech

ClinicalTrials.gov Identifier:

NCT00299104

First received: March 2, 2006

Last updated: July 20, 2012

Last verified: July 2012

History of Changes

Results First Received: November 16, 2009

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Drug: folate Drug: methotrexate Drug: methylprednisolone Drug: placebo Drug: rituximab

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

Description

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.

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

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

Participant Flow: Overall Study

	Placebo + Methotrexate	Rituximab (0.5 g x 2) + Methotrexate	Rituximab (1.0 g x 2) + Methotrexate
STARTED	251	252	252
Safety/ITT: Received Study Drug	249	249	250
Completed Week 24	227	240	241
Completed Week 52	213	227	232
Completed Week 104	178	213	216
COMPLETED	62 ^[1]	77	80
NOT COMPLETED	189	175	172
Adverse Event	14	9	7
Death	1	1	1
Insufficient therapeutic response	34	13	8
Failure to return	9	8	8
Violation of selection criteria	1	2	0
Protocol Violation	1	1	0
Refused treatment	9	2	2
Withdrew consent	14	19	9
Administrative reasons	106	120	137

[1]	Completed Week 152

Baseline Characteristics

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Reporting Groups

	Description
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.
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
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
Total	Total of all reporting groups

Baseline Measures

	Placebo + Methotrexate	Rituximab (0.5 g x 2) + Methotrexate	Rituximab (1.0 g x 2) + Methotrexate	Total
Number of Participants [units: participants]	249	249	250	748
Age ^[1] [units: years] Mean ± Standard Deviation	48.06 ± 12.692	47.87 ± 13.391	47.89 ± 13.324	47.94 ± 13.136
Gender ^[1] [units: participants]
Female	192	203	212	607
Male	57	46	38	141

[1]	Intent-to-treat population

Outcome Measures

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1. Primary:

Change From Baseline in Modified Total Sharp Score (mTSS) From Screening at Week 52 [ Time Frame: Baseline and week 52 ]

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2. Secondary:

Change From Baseline in Modified Sharp Erosion Score at Week 52 [ Time Frame: Baseline and week 52 ]

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3. Secondary:

Percentage of Patients Without Radiographic Progression at Week 52 [ Time Frame: Baseline, Week 52 ]

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4. Secondary:

Percentage of Patients Without Radiographic Progression in Total Erosion Score at Week 52 [ Time Frame: Baseline, Week 52 ]

Show Outcome Measure 4

5. Secondary:

Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 52 [ Time Frame: Baseline and week 52 ]

Show Outcome Measure 5

6. Secondary:

Change From Baseline in the Modified Total Sharp Score at Week 24 [ Time Frame: Baseline, Week 24 ]

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7. Secondary:

Change From Baseline in the Total Erosion Score at Week 24 [ Time Frame: Baseline, Week 24 ]

Show Outcome Measure 7

8. Secondary:

Change From Baseline in Modified Joint Space Narrowing (JSN) Score at Week 24 [ Time Frame: Baseline, Week 24 ]

Show Outcome Measure 8

9. Secondary:

Percentage of Participants Without Radiographic Progression at Week 24 [ Time Frame: Baseline, Week 24 ]

Show Outcome Measure 9

10. Secondary:

Percentage of Participants With American College of Rheumatology (ACR) ACR50 Response at Week 52 [ Time Frame: Week 52 ]

Show Outcome Measure 10

11. Secondary:

Change From Baseline in the Disease Activity Score 28 Joint Count- Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 52 [ Time Frame: Baseline, Week 52 ]

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12. Secondary:

Percentage of Participants With American College of Rheumatology (ACR) ACR70 Response at Week 52 [ Time Frame: Baseline, Week 52 ]

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13. Secondary:

Percentage of Participants With DAS28-ESR Remission at Week 52 [ Time Frame: Week 52 ]

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14. Secondary:

Percentage of Participants With European League Against Rheumatism (EULAR) Good Response at Week 52 [ Time Frame: Baseline, Week 52 ]

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15. Secondary:

The Percentage of Participants With Major Clinical Response at Week 52 [ Time Frame: Week 52 ]

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16. Secondary:

Percentage of Participants With DAS28-ESR Low Disease Activity at Week 52 [ Time Frame: Week 52 ]

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17. Secondary:

Percentage of Participants With American College of Rheumatology (ACR) ACR20 Response at Week 52 [ Time Frame: Baseline, Week 52 ]

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18. Secondary:

Percentage of Participants With American College of Rheumatology (ACR) ACR90 Response at Week 52 [ Time Frame: Baseline, Week 52 ]

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19. Secondary:

Change in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Score From Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]

Show Outcome Measure 19

20. Secondary:

Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 [ Time Frame: Baseline, Week 52 ]

Show Outcome Measure 20

21. Secondary:

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 ]

Show Outcome Measure 21

22. Secondary:

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 ]

Show Outcome Measure 22

23. Secondary:

Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 [ Time Frame: Baseline, Week 52 ]

Hide Outcome Measure 23

Measure Type	Secondary
Measure Title	Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52
Measure Description	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
Time Frame	Baseline, Week 52
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat (ITT) population includes all randomized participants who received at least one infusion. Last observation carried forward.

Reporting Groups

Description

Placebo + Methotrexate

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

Rituximab (0.5 g x 2) + Methotrexate

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

Rituximab (1.0 g x 2) + Methotrexate

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

Measured Values

	Placebo + Methotrexate	Rituximab (0.5 g x 2) + Methotrexate	Rituximab (1.0 g x 2) + Methotrexate
Number of Participants Analyzed [units: participants]	249	249	250
Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52 [units: Percentage of participants]
Improved	77.1	86.7	86.8
Unchanged	14.1	8.8	8.0
Worsened	8.4	3.6	4.4
Not Assessable	0.4	0.8	0.8

No statistical analysis provided for Percentage of Participants With Categorical Change in Health Assessment Questionnaire- Disability Index (HAQ-DI) From Baseline at Week 52

24. Secondary:

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 ]

Show Outcome Measure 24

25. Secondary:

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 ]

Show Outcome Measure 25

26. Secondary:

Change From Baseline in the Modified Total Sharp Score at Week 104 [ Time Frame: Baseline, Week 104 ]

Show Outcome Measure 26

27. Secondary:

Change From Baseline in the Total Erosion Score at Week 104 [ Time Frame: Baseline, Week 104 ]

Show Outcome Measure 27

28. Secondary:

Percentage of Participants Without Radiographic Progression at Week 104 [ Time Frame: Baseline, Week 104 ]

Show Outcome Measure 28

29. Secondary:

Percentage of Participants Without Radiographic Progression in the Total Erosion Score at Week 104 [ Time Frame: Week 104 ]

Show Outcome Measure 29

30. Secondary:

Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 104 [ Time Frame: Baseline, Week 104 ]

Show Outcome Measure 30

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Medical Communications
Organization: Genentech, Inc.
phone: 800-821-8590

No publications provided by Genentech

Publications automatically indexed to this study:

Tak PP, Rigby W, Rubbert-Roth A, Peterfy C, van Vollenhoven RF, Stohl W, Healy E, Hessey E, Reynard M, Shaw T. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Ann Rheum Dis. 2012 Mar;71(3):351-7. Epub 2011 Oct 19.

Rigby W, Ferraccioli G, Greenwald M, Zazueta-Montiel B, Fleischmann R, Wassenberg S, Ogale S, Armstrong G, Jahreis A, Burke L, Mela C, Chen A. Effect of rituximab on physical function and quality of life in patients with rheumatoid arthritis previously untreated with methotrexate. Arthritis Care Res (Hoboken). 2011 May;63(5):711-20.

Tak PP, Rigby WF, Rubbert-Roth A, Peterfy CG, van Vollenhoven RF, Stohl W, Hessey E, Chen A, Tyrrell H, Shaw TM; IMAGE Investigators. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis. 2011 Jan;70(1):39-46. Epub 2010 Oct 11.

Responsible Party:	Genentech
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:	July 20, 2012
Health Authority:	United States: Food and Drug Administration

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