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Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis (RAVE)

This study has been completed.
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
Genentech, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00104299
First received: February 24, 2005
Last updated: October 17, 2013
Last verified: October 2013
Results First Received: February 2, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Vasculitis
Wegener's Granulomatosis
Microscopic Polyangiitis
Interventions: Drug: Rituximab plus cyclophosphamide placebo (rituximab group)
Drug: Cyclophosphamide plus rituximab placebo (control group)
Drug: Azathioprine
Drug: Methylprednisolone (or other glucocorticoid)
Drug: Prednisone

  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
Eight centers in the United States and one center in the Netherlands (Groningen) enrolled 197 Antineutrophil cytoplasmic antibodies (ANCA)-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis between December 30, 2004 and June 30, 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.

Reporting Groups
  Description
Rituximab Participants received intravenous rituximab (Rituxan, Genentech) (at a dose of 375 mg per square meter of body-surface area once weekly for 4 weeks) plus daily placebo−cyclophosphamide. Refer to section titled “Detailed Description” for additional treatment information.
Control Group Participants received placebo−rituximab infusions plus daily cyclophosphamide (2 mg per kilogram of body weight, adjusted for renal insufficiency). Refer to section titled “Detailed Description” for additional treatment information.

Participant Flow:   Overall Study
    Rituximab     Control Group  
STARTED     99     98  
COMPLETED     90 [1]   88 [1]
NOT COMPLETED     9     10  
Adverse Event                 3                 1  
Death                 2                 2  
Withdrawal by Subject                 2                 6  
Physician Decision                 1                 1  
To have renal transplant                 1                 0  
[1] Number of participants who completed 18 months post-randomization



  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.
No text entered.

Reporting Groups
  Description
Rituximab Participants received intravenous rituximab (Rituxan, Genentech) (at a dose of 375 mg per square meter of body-surface area once weekly for 4 weeks) plus daily placebo−cyclophosphamide. Refer to section titled “Detailed Description” for additional treatment information.
Control Group Participants received placebo−rituximab infusions plus daily cyclophosphamide (2 mg per kilogram of body weight, adjusted for renal insufficiency). Refer to section titled “Detailed Description” for additional treatment information.
Total Total of all reporting groups

Baseline Measures
    Rituximab     Control Group     Total  
Number of Participants  
[units: participants]
  99     98     197  
Age  
[units: participants]
     
<=18 years     3     3     6  
Between 18 and 65 years     60     76     136  
>=65 years     36     19     55  
Age  
[units: years]
Mean ± Standard Deviation
  54.0  ± 16.8     51.5  ± 14.1     52.8  ± 15.5  
Gender  
[units: participants]
     
Female     52     45     97  
Male     47     53     100  
Region of Enrollment  
[units: participants]
     
United States     91     90     181  
Netherlands     8     8     16  
BVAS/WG [1]
[units: scoreĀ units]
Mean ± Standard Deviation
  8.1  ± 2.8     8.0  ± 3.4     8.0  ± 3.1  
VDI [2]
[units: scoreĀ units]
Mean ± Standard Deviation
  1.4  ± 1.8     1.0  ± 1.4     1.2  ± 1.7  
[1] The Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (WG) is a validated disease activity index. The BVAS/WG is designed to document new or worsening clinically active vasculitis and consists of a set of items divided into nine organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease. In this study, the primary end point was a BVAS/WG score of 0 and successful completion of the prednisone taper at 6 months.
[2] Vasculitis Damage Index. The VDI is a validated measure for damage assessment in vasculitis. The index comprises 64 items of damage (divided into 11 organ based systems) representative of damage incurred to patients with systemic vasculitis. Scores for this index range from 0 to 64, with higher scores indicating more severe damage.



  Outcome Measures
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1.  Primary:   Disease Remission   [ Time Frame: 6 months post-randomization ]

2.  Secondary:   Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy   [ Time Frame: Through common close-out (defined as 18 months after the last participant is enrolled in the trial) ]

3.  Secondary:   Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization   [ Time Frame: 6 months post-randomization ]

4.  Secondary:   The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups   [ Time Frame: 18 months post-randomization ]

5.  Secondary:   The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups   [ Time Frame: 18 months post-randomization ]

6.  Secondary:   Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups   [ Time Frame: 18 months post-randomization ]

7.  Secondary:   Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups   [ Time Frame: 18 months post-randomization ]
  Hide Outcome Measure 7

Measure Type Secondary
Measure Title Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups
Measure Description

Time to complete remission is defined as the number of days from baseline visit (Visit 1) to a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)[1] of 0 and completing taper of glucocorticoid by 6 months post-randomization.

[1] The BVAS/WG is a disease activity index designed to document new or worsening clinically active vasculitis consisting of items divided into 9 organ based systems. BVAS/WG scores range from 0 to 63, with higher scores indicating more active disease

Time Frame 18 months post-randomization  
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

Reporting Groups
  Description
Rituximab Participants received intravenous rituximab (Rituxan, Genentech) (at a dose of 375 mg per square meter of body-surface area once weekly for 4 weeks) plus daily placebo−cyclophosphamide. Refer to section titled “Detailed Description” for additional treatment information.
Control Group Participants received placebo−rituximab infusions plus daily cyclophosphamide (2 mg per kilogram of body weight, adjusted for renal insufficiency). Refer to section titled “Detailed Description” for additional treatment information.

Measured Values
    Rituximab     Control Group  
Number of Participants Analyzed  
[units: participants]
  99     98  
Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups  
[units: Days]
Number ( 95% Confidence Interval )
   
25% Quartile (95%CI)     176  
  ( 173 to 177 )  
  177  
  ( 175 to 178 )  
50% Quartile (95%CI)     180  
  ( 178 to 182 )  
  183  
  ( 180 to 187 )  
75% Quartile (95%CI)     189  
  ( 183 to 253 )  
  266  
  ( 190 to 287 )  


Statistical Analysis 1 for Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.147
Cox Proportional Hazard [4] 1.3
95% Confidence Interval ( 0.9 to 1.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  The log-rank test assesses the difference between the two treatment arms in the pattern of achieving complete remission
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  The hazard ratio and confidence interval are based on a Cox proportional hazard model comparing rituximab to the control group, adjusting for clinical study site, ANCA type, and glucocorticoid use prior to baseline.



8.  Post-Hoc:   Number of Subjects Experiencing Serious Adverse Events   [ Time Frame: Randomization to censor at Crossover, Open-label or Best Medical Judgment (up to 18 months post-randomization) ]


  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
No text entered.


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