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

This study has been completed.
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
Genentech
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 ]
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Measure Type Primary
Measure Title Disease Remission
Measure Description A Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) score of 0 with prednisone taper successfully completed at six months. The BVAS/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.
Time Frame 6 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 (ITT) sample with worst case imputation

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  
Disease Remission  
[units: Participants]
  63     52  


Statistical Analysis 1 for Disease Remission
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] 95.1% CI of difference
P Value [4] <0.001
Difference between group success rates [5] 10.6
95.1% Confidence Interval ( -3.2 to 24.3 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  In calculating the sample size, we assumed that the percentage of patients in both treatment groups would achieve disease remission off prednisone by 6 months was 70%. We specified a non-inferiority margin of -20% on the difference in remission rates (rituximab rate minus cyclophosphamide rate) and a one-sided 0.025 level test. Assuming a 10% dropout rate, RAVE required 100 patients in each arm to have 83% power to conclude non-inferiority.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  non-inferiority margin of -20%
[3] Other relevant method information, such as adjustments or degrees of freedom:
  Calculate 95.1% CI around the difference in success rates between arms. Lower bound above non-inferiority margin of -20% indicates non-inferiority.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is adjusted for interim analysis using a Lan-DeMets alpha spending function with an O’Brien-Fleming boundary, allocating 0.003 alpha to the interim analysis and 0.049 alpha to the final analysis.
[5] Other relevant estimation information:
  No text entered.



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 ]

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


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.


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
No text entered.  


Results Point of Contact:  
Name/Title: Associate Director, Clinical Research Program
Organization: DAIT/NIAID
phone: (301) 594-7669
e-mail: DAITClinicalTrialsGov@niaid.nih.gov


Publications of Results:

Other Publications:

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00104299     History of Changes
Other Study ID Numbers: DAIT ITN021AI
Study First Received: February 24, 2005
Results First Received: February 2, 2011
Last Updated: October 17, 2013
Health Authority: United States: Food and Drug Administration