A Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate Compared to Methotrexate Alone in Patients With Active Rheumatoid Arthritis (SERENE)

This study has been completed.
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00299130
First received: March 3, 2006
Last updated: January 11, 2016
Last verified: January 2016
Results First Received: February 21, 2013  
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
A total of 511 participants were recruited and randomized between 27 Oct 2005 and 15 Nov 2006. Of these, 2 participants were randomized but received no infusions (one violated inclusion criteria and the other was randomized to rituximab 2 x 1.0 gram [g] + methotrexate [MTX] but failed to return). A total of 509 participants were treated.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 509 participants, one participant was randomized first to rituximab 2 x 1.0 g + MTX and then to rituximab 2 x 0.5 g + MTX. No assessments were recorded or medication given after first randomization and all data used in analyses was following the second randomization; hence, participant is included only in rituximab 2 x 0.5 g + MTX arm.

Reporting Groups
  Description
Placebo + MTX

Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Rituximab 2 x 0.5 g + MTX

Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone.

Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Rituximab 2 x 1.0 g + MTX

Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone.

Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.


Participant Flow for 3 periods

Period 1:   Treatment Period (up to 5 Years)
    Placebo + MTX     Rituximab 2 x 0.5 g + MTX     Rituximab 2 x 1.0 g + MTX  
STARTED     172     168     171  
Treated     172 [1]   167     170  
Completed 24 Weeks     159     162     166  
Completed 48 Weeks     155     157     158  
Completed 144 Weeks     133     138     132  
COMPLETED     119     125     121  
NOT COMPLETED     53     43     50  
Adverse Event                 13                 8                 13  
Death                 1                 3                 1  
Insufficient Therapeutic Response                 19                 6                 6  
Protocol Violation                 0                 1                 0  
Refused Treatment                 12                 12                 19  
Failure to Return                 4                 6                 6  
Reason not Specified                 4                 6                 4  
Withdrawal by Subject                 0                 1                 1  
[1] 155 participants in placebo arm switched to active therapy (rituximab 2 x 0.5g) between Weeks 16-48.

Period 2:   Safety Follow-up (SFU) (48 Weeks)
    Placebo + MTX     Rituximab 2 x 0.5 g + MTX     Rituximab 2 x 1.0 g + MTX  
STARTED     167     165     168  
COMPLETED     122     120     123  
NOT COMPLETED     45     45     45  
Administrative/Other                 4                 9                 4  
Death                 4                 5                 3  
Did not Co-operate                 1                 1                 2  
Failure to Return                 14                 7                 15  
No SFU Week 48 Date Recorded                 0                 1                 0  
Withdrawal by Subject                 22                 22                 21  

Period 3:   Extended SFU (ESFU) (up to 5.1 Years)
    Placebo + MTX     Rituximab 2 x 0.5 g + MTX     Rituximab 2 x 1.0 g + MTX  
STARTED     0     82     44  
COMPLETED     0     74     38  
NOT COMPLETED     0     8     6  
Death                 0                 3                 0  
Failure to Return                 0                 2                 2  
Did not Cooperate/Withdrew Consent                 0                 3                 4  



  Baseline Characteristics
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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.
Safety population included all randomized participants who received any part of an infusion.

Reporting Groups
  Description
Placebo + MTX

Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Rituximab 2 x 0.5 g + MTX

Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone.

Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Rituximab 2 x 1.0 g + MTX

Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone.

Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study.

All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Total Total of all reporting groups

Baseline Measures
    Placebo + MTX     Rituximab 2 x 0.5 g + MTX     Rituximab 2 x 1.0 g + MTX     Total  
Number of Participants  
[units: participants]
  172     167     170     509  
Age  
[units: years]
Mean (Standard Deviation)
  52.16  (12.39)     51.91  (12.93)     51.30  (12.64)     51.80  (12.64)  
Gender  
[units: participants]
       
Female     147     133     138     418  
Male     25     34     32     91  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24   [ Time Frame: Baseline and Week 24 ]

2.  Secondary:   Percentage of Participants With an ACR50 Response at Week 24   [ Time Frame: Baseline and Week 24 ]

3.  Secondary:   Percentage of Participants With an ACR70 Response at Week 24   [ Time Frame: Baseline and Week 24 ]

4.  Secondary:   Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24   [ Time Frame: Baseline and Week 24 ]

5.  Secondary:   Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24   [ Time Frame: Baseline and Week 24 ]

6.  Secondary:   Percent Change From Baseline in Swollen Joint Count   [ Time Frame: Baseline, Week 24 and Week 48 ]

7.  Secondary:   Percent Change From Baseline in Tender Joint Count   [ Time Frame: Baseline, Week 24 and Week 48 ]

8.  Secondary:   Percent Change From Baseline in Patient's Global Assessment of Disease Activity   [ Time Frame: Baseline, Week 24 and Week 48 ]

9.  Secondary:   Percent Change From Baseline in Patient’s Pain Assessment   [ Time Frame: Baseline, Week 24 and Week 48 ]

10.  Secondary:   Percent Change From Baseline in Physician’s Global Assessment of Disease Activity   [ Time Frame: Baseline, Week 24 and Week 48 ]

11.  Secondary:   Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

12.  Secondary:   Percent Change From Baseline in C-Reactive Protein   [ Time Frame: Baseline, Week 24 and Week 48 ]

13.  Secondary:   Percent Change From Baseline in Erythrocyte Sedimentation Rate   [ Time Frame: Baseline, Week 24 and Week 48 ]

14.  Secondary:   Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)   [ Time Frame: Baseline, Week 24 and Week 48 ]

15.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

16.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

17.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

18.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

19.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

20.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

21.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

22.  Secondary:   Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score   [ Time Frame: Baseline, Week 24 and Week 48 ]

23.  Secondary:   Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores   [ Time Frame: Baseline, Week 24 and Week 48 ]

24.  Secondary:   Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24   [ Time Frame: Week 24 ]

25.  Secondary:   Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24   [ Time Frame: Baseline and Week 24 ]

26.  Secondary:   Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48   [ Time Frame: Baseline and Week 48 ]

27.  Secondary:   Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48   [ Time Frame: Baseline and Week 48 ]

28.  Secondary:   Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48   [ Time Frame: Week 48 ]

29.  Secondary:   Percentage of Participants With an ACR50 Response at Week 48   [ Time Frame: Baseline and Week 48 ]

30.  Secondary:   Percentage of Participants With an ACR70 Response at Week 48   [ Time Frame: Baseline and Week 48 ]

31.  Post-Hoc:   Time to Repletion of Peripheral CD19+ B-cells   [ Time Frame: Beginning of the first infusion (Day 1) in the last treatment cycle until repletion or the end of the study (approximately 6.5 years) ]

32.  Post-Hoc:   Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment   [ Time Frame: Baseline (pre-rituximab), Beginning of the safety follow-up period to the end of the study (approximately 6 years) (post-rituximab) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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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  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:
unchecked 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.
unchecked 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.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffman-La Roche
phone: 800-821-8590
e-mail: genentech@druginfo.com


Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00299130     History of Changes
Other Study ID Numbers: U2973g
WA17045 ( Other Identifier: F. Hoffmann-La Roche )
Study First Received: March 3, 2006
Results First Received: February 21, 2013
Last Updated: January 11, 2016
Health Authority: United States: Food and Drug Administration