Safety and Tolerability of Rituxan With Methotrexate and Etanercept or Methotrexate and Adalimumab in Patients With Active Rheumatoid Arthritis

This study has been completed.

Sponsor:

Collaborators:

Hoffmann-La Roche

Genentech

Information provided by:

Biogen Idec

ClinicalTrials.gov Identifier:

NCT00298272

First received: March 1, 2006

Last updated: June 7, 2012

Last verified: September 2010

History of Changes

Results First Received: April 20, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator); Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Biological: Rituximab Other: Placebo Drug: Methotrexate Drug: Etanercept Drug: Adalimumab Drug: Methylprednisolone Dietary Supplement: Folate Drug: Glucocorticoid

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
Overall, 54 participants were enrolled at 17 sites in the United States, 51 received treatment, and 49 completed the Week 24 requirements of the study. The first participant was treated on 10 May 2006, and the 24-week primary endpoint treatment period ended 15 April 2009. An open-label treatment period is ongoing at the time of this posting.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Three participants were enrolled in the study but never received treatment. Of those 3 participants, 2 never returned to the study site for treatment and 1 was determined to be ineligible before treatment began.

Reporting Groups

	Description
Rituximab + MTX + TNF Inhibitor	The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. As background therapy, participants were to receive a tumor necrosis factor (TNF) inhibitor; either etanercept 50 mg by subcutaneous injection (SC) weekly or adalimumab 40 mg SC once every 2 weeks. Additionally, participants were to receive methotrexate (MTX) 15 to 25 mg by mouth or by intramuscular injection (IM) weekly. All background therapies were to be administered at a stable dose for the duration of the study.
Placebo + MTX + TNF Inhibitor	The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. As background therapy, participants were to receive a TNF inhibitor; either etanercept 50 mg SC weekly or adalimumab 40 mg SC once every 2 weeks. Additionally, participants were to receive MTX 15 to 25 mg by mouth or IM weekly. All background therapies were to be administered at a stable dose for the duration of the study.

Description

Rituximab + MTX + TNF Inhibitor

The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.

As background therapy, participants were to receive a tumor necrosis factor (TNF) inhibitor; either etanercept 50 mg by subcutaneous injection (SC) weekly or adalimumab 40 mg SC once every 2 weeks. Additionally, participants were to receive methotrexate (MTX) 15 to 25 mg by mouth or by intramuscular injection (IM) weekly. All background therapies were to be administered at a stable dose for the duration of the study.

Placebo + MTX + TNF Inhibitor

The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.

As background therapy, participants were to receive a TNF inhibitor; either etanercept 50 mg SC weekly or adalimumab 40 mg SC once every 2 weeks. Additionally, participants were to receive MTX 15 to 25 mg by mouth or IM weekly. All background therapies were to be administered at a stable dose for the duration of the study.

Participant Flow: Overall Study

	Rituximab + MTX + TNF Inhibitor	Placebo + MTX + TNF Inhibitor
STARTED	33 ^[1]	18
COMPLETED	31	18
NOT COMPLETED	2	0
Adverse Event	2	0

[1]	Thirty-six participants were enrolled but only 33 received treatment (see Pre-Assignment Details).

Baseline Characteristics

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Reporting Groups

	Description
Rituximab + MTX + TNF Inhibitor	The rituximab treatment group received rituximab 500 mg IV on Day 1 and Day 15.
Placebo + MTX + TNF Inhibitor	The placebo treatment group received saline solution IV on Day 1 and Day 15.
Total	Total of all reporting groups

Baseline Measures

	Rituximab + MTX + TNF Inhibitor	Placebo + MTX + TNF Inhibitor	Total
Number of Participants [units: participants]	33	18	51
Age [units: Years] Mean ± Standard Deviation	49.7 ± 12.1	50.4 ± 11.4	50.0 ± 11.7
Gender [units: Participants]
Female	28	17	45
Male	5	1	6
Years since rheumatoid arthritis (RA) diagnosis [units: Years] Mean ± Standard Deviation	10.3 ± 6.7	10.7 ± 7.5	10.5 ± 6.9
Prior treatment with TNF inhibitors (1 or more) [units: Participants]	33	18	51
C-Reactive Protein [units: Milligrams per decilitre (mg/dL)] Mean ( Full Range )	0.97 ( 0.0 to 6.3 )	0.83 ( 0.1 to 3.3 )	0.92 ( 0.0 to 6.3 )
Swollen and tender joints [units: Joint counts] Mean ( Full Range )
Swollen joints	16.9 ( 5 to 43 )	14.2 ( 6 to 30 )	16.0 ( 5 to 43 )
Tender joints	25.6 ( 5 to 56 )	22.8 ( 9 to 63 )	24.6 ( 5 to 63 )

Outcome Measures

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1. Primary:

Proportion of Participants With at Least One Serious Infection [ Time Frame: Through Week 24 ]

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2. Secondary:

Proportion of Participants Achieving an American College of Rheumatology (ACR)20 Response. [ Time Frame: Through Week 24 ]

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3. Secondary:

Proportion of Participants Achieving an ACR50 Response [ Time Frame: Through Week 24 ]

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4. Secondary:

Proportion of Participants Achieving an ACR70 Response [ Time Frame: Through Week 24 ]

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5. Other Pre-specified:

Proportion of Participants With at Least One Grade 3 or Grade 4 Infection [ Time Frame: Through Week 24 ]

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6. Other Pre-specified:

Duration of Infections [ Time Frame: Through Week 24 ]

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7. Other Pre-specified:

Proportion of Participants With at Least One Infection [ Time Frame: Through Week 24 ]

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Measure Type	Other Pre-specified
Measure Title	Proportion of Participants With at Least One Infection
Measure Description	No text entered.
Time Frame	Through Week 24
Safety Issue	Yes

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.
The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo. This population was used for the analyses of all safety, efficacy, and baseline subject status data.

Reporting Groups

	Description
Rituxan + MTX + TNF Inhibitor	The rituximab treatment group received rituximab 500 mg IV on Day 1 and Day 15 of the study.
Placebo + MTX + TNF Inhibitor	The placebo treatment group received saline solution IV on Day 1 and Day 15 of the study.

Measured Values

	Rituxan + MTX + TNF Inhibitor	Placebo + MTX + TNF Inhibitor
Number of Participants Analyzed [units: participants]	33	18
Proportion of Participants With at Least One Infection [units: Proportion of participants by group]	0.55	0.61

No statistical analysis provided for Proportion of Participants With at Least One Infection

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: A copy of the disclosure must be given to Biogen Idec for review at least 60 days before disclosure to another party. For multi-center studies, no disclosure is permitted until results from all centers have been received and analyzed, or the study has been abandoned at all centers. If a committee of Investigators is formed for results publication, no separate publication is permitted until the initial committee publication or until a decision is reached by the committee not to publish.

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
The study was planned for 60 participants, but enrollment was stopped at 54. Also, the study was not designed or powered to test for efficacy and no formal statistical analyses of efficacy results (ACR20/50/70) were performed.

Results Point of Contact:

Name/Title: Biogen Idec Study Medical Director
Organization: Biogen Idec
phone: +1 617 679-2000

No publications provided by Biogen Idec

Publications automatically indexed to this study:

Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011 Mar;63(3):622-32.

Responsible Party:	Biogen Idec MD, Biogen Idec
ClinicalTrials.gov Identifier:	NCT00298272 History of Changes
Other Study ID Numbers:	102-RA-201
Study First Received:	March 1, 2006
Results First Received:	April 20, 2010
Last Updated:	June 7, 2012
Health Authority:	United States: Food and Drug Administration

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