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
  Hide Participant Flow

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 ]

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) ]

Measure Type Secondary
Measure Title Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy
Measure Description The adverse event rate for the following events considered related to vasculitis: Death; Grade 2 or higher leukopenia or thrombocytopenia; Grade 3 or higher infections; Hemorrhagic cystitis (grade 2 or lower needs confirmation by cytoscopy); Malignancy; Venous thromboembolic event (deep venous thrombosis or pulmonary embolism); Hospitalization resulting either from the disease or from a complication due to study treatment; Infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions (including cytokine release allergic reaction); Cerebrovascular accident
Time Frame Through common close-out (defined as 18 months after the last participant is enrolled in the trial)  
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.
Safety Sample

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  
Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy  
[units: participants]
   
Death     2     2  
Grade 2 or Higher Leukopenia     7     23  
Grade 2 or Higher Thrombocytopenia     4     1  
Grade 3 or Higher Infections     18     16  
Hemorrhagic Cystitis (Grade 2 or Lower)     2     1  
Malignancy     5     2  
Venous Thromboembolic Event     6     8  
Hospitalization Resulting from the Disease     16     7  
Cerebrovascular Accident (CVA)     1     1  
Infusion Reactions Leading to Infusion Disc.     1     0  


Statistical Analysis 1 for Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy
Groups [1] All groups
Method [2] Poisson regression model
P Value [3] 0.927
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Participant-months are defined as duration in months from the first study drug dosing date to the last date of the participant in the protocol. The rate of selected AEs is defined as the total number of selected AEs divided by total participant-months, and indicates the number of events per participant per month on average. Participants are grouped according to their originally received treatment.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] 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 from the Poisson regression model adjusting for clinical study site and ANCA type. The natural logarithm of participant-months is used as an offset in this model



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 ]

Measure Type Secondary
Measure Title Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization
Measure Description

The 2-sided 95% CI of the percentage of participants who have a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)[1] of 0 and have successfully completed the glucocorticoid taper by 6 months post-randomization and the 2-sided 95% CI of the difference between two arms for assessing the superiority of rituximab to control

[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 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.
Safety Sample

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  
Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization  
[units: participants]
  62     51  


Statistical Analysis 1 for Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization
Groups [1] All groups
Method [2] Chi-squared
P Value [3] 0.133
95.1% Confidence Interval of Difference [4] 10.6
95.1% Confidence Interval ( -3.2 to 24.4 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The p-value is from a chi-square test.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  At 6 months, the confidence interval is 95.1%.
[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:
  No text entered.



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 ]

Measure Type Secondary
Measure Title The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Measure Description

Duration of complete remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)[1] of 0 and a completing taper of Prednisone to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing.

[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  
The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups  
[units: Days]
Number ( 95% Confidence Interval )
   
25% Quartile (95%CI)     243  
  ( 172 to NA ) [1]
  230  
  ( 145 to NA ) [1]
50% Quartile (95%CI)     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
75% Quartile (95%CI)     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] Some survival parameters are not estimable when there are small numbers of events


Statistical Analysis 1 for The Duration of Complete Remission (BVAS=0, Off Glucocorticoids), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.761
Cox Proportional Hazard [4] 0.9
95% Confidence Interval ( 0.5 to 1.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Participants are censored at the time of crossover, open label rituximab, or best medical judgement, if applicable. If a participant has no flare after complete remission prior to their Month 18 visit, the duration is censored at the date of the Month 18 Visit
[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 flaring pattern after 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:
  The log-rank test assesses the difference between the two treatment arms in the flaring pattern after complete remission
[4] Other relevant estimation information:
  No text entered.



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 ]

Measure Type Secondary
Measure Title The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Measure Description Duration of remission is defined as a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)[1] of 0 and a completing taper of glucocorticoid by 6 months post-randomization to the first flare, BVAS/WG score of greater than 0, or an increase in Prednisone dosing.
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  
The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups  
[units: Days]
Number ( 95% Confidence Interval )
   
25% Quartile (95%CI)     246  
  ( 152 to 335 )  
  168  
  ( 141 to 300 )  
50% Quartile (95%CI)     NA  
  ( 403 to NA ) [1]
  NA  
  ( 353 to NA ) [1]
75% Quartile (95%CI)     NA  
  ( NA to NA ) [1]
  NA  
  ( NA to NA ) [1]
[1] Some survival parameters are not estimable when there are small numbers of events


Statistical Analysis 1 for The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.861
Cox Proportional Hazard [4] 0.9
95% Confidence Interval ( 0.6 to 1.5 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Participants are censored at the time of crossover, open label rituximab, or best medical judgement, if applicable. If a participant has no flare after complete remission prior to their Month 18 visit, the duration is censored at the date of the Month 18 Visit
[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 flaring pattern after 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:
  No text entered.



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

Measure Type Secondary
Measure Title Time to Remission (BVAS=0) 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.

[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 Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups  
[units: Days]
Number ( 95% Confidence Interval )
   
25% Quartile (95%CI)     30  
  ( 29 to 34 )  
  29  
  ( NA to NA ) [1]
50% Quartile (95%CI)     57  
  ( 41 to 63 )  
  43  
  ( 30 to 58 )  
75% Quartile (95%CI)     119  
  ( 69 to 123 )  
  112  
  ( 61 to 120 )  
[1] Confidence limits not estimable due to no variability around quartile


Statistical Analysis 1 for Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.497
Cox Proportional Hazard [4] 1.0
95% Confidence Interval ( 0.7 to 1.3 )
[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 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.



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 ]

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) ]

Measure Type Post-Hoc
Measure Title Number of Subjects Experiencing Serious Adverse Events
Measure Description Number of subjects according to originally received treatment that experienced a serious adverse event through 18 months post-randomization or prior to being censored from analyses due to crossover, switching to open-label treatment, or best medical judgment for censor. Events are categorized by coded system organ classes (SOC). Within each SOC, a participant was counted once if the participant reported one or more events coded to that SOC.
Time Frame Randomization to censor at Crossover, Open-label or Best Medical Judgment (up to 18 months post-randomization)  
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.
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  
Number of Subjects Experiencing Serious Adverse Events  
[units: participants]
   
# Participants with at least one SAE     42     37  
Blood and Lymphatic System Disorders     4     5  
Cardiac Disorders     2     2  
Eye Disorders     1     1  
Gastrointestinal Disorders     4     1  
General Disorders and Administration Site     5     3  
Immune System Disorders     2     2  
Infections and Infestations     12     12  
Injury, Poisoning, and Procedural Complications     2     0  
Investigations     2     0  
Metabolism and Nutrition Disorders     2     2  
Musculoskeletal and Connective Tissue Disorders     2     3  
Neoplasms Benign, Malignant, and Unspecified     1     2  
Nervous System Disorders     1     0  
Pregnancy, Puerperium, and Perinatal Conditions     1     0  
Psychiatric Disorders     1     1  
Renal and Urinary Disorders     4     3  
Respiratory, Thoracic, and Mediastinal Disorders     8     8  
Vascular Disorders     1     7  


Statistical Analysis 1 for Number of Subjects Experiencing Serious Adverse Events
Groups [1] All groups
Method [2] Chi-squared
P Value [3] 0.504
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Proportions of subjects experiencing a serious adverse event through 18 months and prior to censoring for open-label, crossover, or best medical judgment according to originally assigned treatment arm were compared using a two-sided Chi-squared test.
[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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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  More Information