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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00104299
Recruitment Status : Completed
First Posted : February 25, 2005
Results First Posted : August 25, 2011
Last Update Posted : April 21, 2017
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
Genentech, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, 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
Enrollment 197
Recruitment Details 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 At a screening visit, participants underwent procedures to establish inclusion/exclusion criteria and then sign the informed consent form.
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 99 98
Completed 90 [1] 88 [1]
Not Completed 9 10
Reason Not Completed
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
Arm/Group Title Rituximab Control Group Total
Hide Arm/Group Description 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. 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 of all reporting groups
Overall Number of Baseline Participants 99 98 197
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 99 participants 98 participants 197 participants
<=18 years
3
   3.0%
3
   3.1%
6
   3.0%
Between 18 and 65 years
60
  60.6%
76
  77.6%
136
  69.0%
>=65 years
36
  36.4%
19
  19.4%
55
  27.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 99 participants 98 participants 197 participants
54.0  (16.8) 51.5  (14.1) 52.8  (15.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 99 participants 98 participants 197 participants
Female
52
  52.5%
45
  45.9%
97
  49.2%
Male
47
  47.5%
53
  54.1%
100
  50.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 99 participants 98 participants 197 participants
United States 91 90 181
Netherlands 8 8 16
BVAS/WG   [1] 
Mean (Standard Deviation)
Unit of measure:  Score units
Number Analyzed 99 participants 98 participants 197 participants
8.1  (2.8) 8.0  (3.4) 8.0  (3.1)
[1]
Measure Description: 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.
VDI   [1] 
Mean (Standard Deviation)
Unit of measure:  Score units
Number Analyzed 99 participants 98 participants 197 participants
1.4  (1.8) 1.0  (1.4) 1.2  (1.7)
[1]
Measure Description: 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.
1.Primary Outcome
Title Disease Remission
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) sample with worst case imputation
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Unit of Measure: Participants
63 52
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments non-inferiority margin of -20%
Statistical Test of Hypothesis P-Value <0.001
Comments 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.
Method 95.1% CI of difference
Comments Calculate 95.1% CI around the difference in success rates between arms. Lower bound above non-inferiority margin of -20% indicates non-inferiority.
Method of Estimation Estimation Parameter Difference between group success rates
Estimated Value 10.6
Confidence Interval 95.1%
-3.2 to 24.3
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Sample
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Unit of Measure: 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
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.927
Comments 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
Method Poisson regression model
Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 6 Months Post-randomization
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Sample
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Unit of Measure: participants
62 51
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments The p-value is from a chi-square test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.133
Comments [Not Specified]
Method Chi-squared
Comments At 6 months, the confidence interval is 95.1%.
Method of Estimation Estimation Parameter 95.1% Confidence Interval of Difference
Estimated Value 10.6
Confidence Interval (2-Sided) 95.1%
-3.2 to 24.4
Estimation Comments [Not Specified]
4.Secondary Outcome
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Days
25% Quartile (95%CI)
243 [1] 
(172 to NA)
230 [1] 
(145 to NA)
50% Quartile (95%CI)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
75% Quartile (95%CI)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Some survival parameters are not estimable when there are small numbers of events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments 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
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.761
Comments The log-rank test assesses the difference between the two treatment arms in the flaring pattern after complete remission
Method Log Rank
Comments The log-rank test assesses the difference between the two treatment arms in the flaring pattern after complete remission
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.9
Confidence Interval (2-Sided) 95%
0.5 to 1.7
Estimation Comments [Not Specified]
5.Secondary Outcome
Title The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Days
25% Quartile (95%CI)
246
(152 to 335)
168
(141 to 300)
50% Quartile (95%CI)
NA [1] 
(403 to NA)
NA [1] 
(353 to NA)
75% Quartile (95%CI)
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
Some survival parameters are not estimable when there are small numbers of events
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments 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
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.861
Comments [Not Specified]
Method Log Rank
Comments The log-rank test assesses the difference between the two treatment arms in the flaring pattern after remission
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.9
Confidence Interval (2-Sided) 95%
0.6 to 1.5
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Days
25% Quartile (95%CI)
30
(29 to 34)
29 [1] 
(NA to NA)
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
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.497
Comments [Not Specified]
Method Log Rank
Comments The log-rank test assesses the difference between the two treatment arms in the pattern of achieving remission
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
0.7 to 1.3
Estimation Comments 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 Outcome
Title Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Days
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)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.147
Comments [Not Specified]
Method Log Rank
Comments The log-rank test assesses the difference between the two treatment arms in the pattern of achieving complete remission
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.3
Confidence Interval (2-Sided) 95%
0.9 to 1.8
Estimation Comments 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 Outcome
Title Number of Subjects Experiencing Serious Adverse Events
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 99 98
Measure Type: Number
Unit of Measure: 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
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rituximab, Control Group
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.504
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame From randomization through common close out (defined as 18 months after the last participant is enrolled in the trial)
Adverse Event Reporting Description Adverse events reported include both disease and non-disease related events by originally assigned treatment. No participants are censored from these results. NCI-CTCAE version 3.0 (published June 10, 2003) was used to grade severity.
 
Arm/Group Title Rituximab Control Group
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Rituximab Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Rituximab Control Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   60/99 (60.61%)      47/98 (47.96%)    
Blood and lymphatic system disorders     
Anaemia † 1  3/99 (3.03%)  3 4/98 (4.08%)  6
Autoimmune thrombocytopenia † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Febrile neutropenia † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Leukopenia † 1  3/99 (3.03%)  5 0/98 (0.00%)  0
Pancytopenia † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Cardiac disorders     
Atrial fibrillation † 1  2/99 (2.02%)  2 0/98 (0.00%)  0
Atrial tachycardia † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Myocardial infarction † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Supraventricular tachycardia † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Ear and labyrinth disorders     
Sudden hearing loss † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Eye disorders     
Keratitis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Ulcerative keratitis † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Gastrointestinal disorders     
Colitis ischaemic † 1  2/99 (2.02%)  2 0/98 (0.00%)  0
Diarrhoea † 1  2/99 (2.02%)  2 0/98 (0.00%)  0
Gastritis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Impaired gastric emptying † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pancreatitis acute † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Upper gastrointestinal haemorrhage † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
General disorders     
Adverse drug reaction † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Asthenia † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Chest pain † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Chills † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Multi-organ failure † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pyrexia † 1  2/99 (2.02%)  2 0/98 (0.00%)  0
Hepatobiliary disorders     
Cholelithiasis † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Immune system disorders     
Anti-neutrophil cytoplasmic antibody positive vasculitis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Drug hypersensitivity † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Hypersensitivity † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Infections and infestations     
Abdominal abscess † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Abscess limb † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Acute sinusitis † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Bronchitis † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Cellulitis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Cellulitis orbital † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Cellulitis staphylococcal † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Central line infection † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Clostridial infection † 1  1/99 (1.01%)  2 0/98 (0.00%)  0
Clostridium difficile colitis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Escherichia infection † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Gastroenteritis viral † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Infective exacerbation of chronic obstructive airways disease † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Influenza † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Lobar pneumonia † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Osteomyelitis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Periorbital cellulitis † 1  0/99 (0.00%)  0 1/98 (1.02%)  2
Pneumocystis jiroveci pneumonia † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Pneumonia † 1  8/99 (8.08%)  10 10/98 (10.20%)  11
Pneumonia bacterial † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Post streptococcal glomerulonephritis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Respiratory tract infection † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Sepsis † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Septic shock † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Skin infection † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Upper respiratory tract infection † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Urinary tract infection † 1  2/99 (2.02%)  2 1/98 (1.02%)  1
Viral upper respiratory tract infection † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Injury, poisoning and procedural complications     
Accidental overdose † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Clavicle fracture † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Fall † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pelvic fracture † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Subdural haematoma † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Investigations     
Blood creatinine increased † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
C-reactive protein increased † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Haemoglobin decreased † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Metabolism and nutrition disorders     
Dehydration † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Gout † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Hypercalcaemia † 1  0/99 (0.00%)  0 2/98 (2.04%)  2
Hypovolaemia † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Type 2 diabetes mellitus † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Bone disorder † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Intervertebral disc protrusion † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Osteoarthritis † 1  1/99 (1.01%)  2 1/98 (1.02%)  1
Osteonecrosis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Spinal column stenosis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder transitional cell carcinoma † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Colon cancer † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Colon cancer metastatic † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Lung neoplasm malignant † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Prostate cancer † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Squamous cell carcinoma of skin † 1  0/99 (0.00%)  0 2/98 (2.04%)  6
Thyroid cancer † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Uterine cancer † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Nervous system disorders     
Cerebrovascular accident † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Haemorrhagic stroke † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Somnolence † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Syncope † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pregnancy † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Psychiatric disorders     
Depression † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Suicidal ideation † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Suicide attempt † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Renal and urinary disorders     
Acute prerenal failure † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Bladder disorder † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Nephrolithiasis † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Renal failure † 1  4/99 (4.04%)  4 2/98 (2.04%)  2
Renal failure acute † 1  2/99 (2.02%)  2 3/98 (3.06%)  3
Renal failure chronic † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Urinary incontinence † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Reproductive system and breast disorders     
Endometriosis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Chronic obstructive pulmonary disease † 1  0/99 (0.00%)  0 1/98 (1.02%)  1
Dyspnoea † 1  2/99 (2.02%)  2 0/98 (0.00%)  0
Interstitial lung disease † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Laryngeal stenosis † 1  2/99 (2.02%)  2 2/98 (2.04%)  3
Lung infiltration † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Pulmonary alveolar haemorrhage † 1  2/99 (2.02%)  2 2/98 (2.04%)  2
Pulmonary embolism † 1  3/99 (3.03%)  3 2/98 (2.04%)  2
Pulmonary haemorrhage † 1  1/99 (1.01%)  1 1/98 (1.02%)  1
Wegener's granulomatosis † 1  8/99 (8.08%)  9 4/98 (4.08%)  5
Vascular disorders     
Aortic dissection † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Deep vein thrombosis † 1  1/99 (1.01%)  1 8/98 (8.16%)  8
Peripheral arterial occlusive disease † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
Thrombosis † 1  1/99 (1.01%)  1 0/98 (0.00%)  0
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Rituximab Control Group
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   97/99 (97.98%)      97/98 (98.98%)    
Blood and lymphatic system disorders     
Anaemia † 1  22/99 (22.22%)  28 18/98 (18.37%)  23
Leukopenia † 1  13/99 (13.13%)  30 39/98 (39.80%)  80
Thrombocytopenia † 1  9/99 (9.09%)  13 5/98 (5.10%)  6
Ear and labyrinth disorders     
Ear pain † 1  7/99 (7.07%)  8 5/98 (5.10%)  5
Endocrine disorders     
Cushingoid † 1  5/99 (5.05%)  6 6/98 (6.12%)  6
Eye disorders     
Vision blurred † 1  4/99 (4.04%)  4 7/98 (7.14%)  7
Gastrointestinal disorders     
Diarrhoea † 1  27/99 (27.27%)  35 20/98 (20.41%)  25
Dyspepsia † 1  7/99 (7.07%)  7 8/98 (8.16%)  8
Gastrooesophageal reflux disease † 1  10/99 (10.10%)  10 6/98 (6.12%)  6
Nausea † 1  25/99 (25.25%)  28 31/98 (31.63%)  41
Vomiting † 1  8/99 (8.08%)  12 13/98 (13.27%)  18
General disorders     
Chest discomfort † 1  6/99 (6.06%)  7 4/98 (4.08%)  4
Chest pain † 1  6/99 (6.06%)  6 4/98 (4.08%)  4
Chills † 1  6/99 (6.06%)  7 5/98 (5.10%)  5
Fatigue † 1  26/99 (26.26%)  32 30/98 (30.61%)  42
Oedema peripheral † 1  22/99 (22.22%)  26 14/98 (14.29%)  19
Pyrexia † 1  10/99 (10.10%)  12 17/98 (17.35%)  25
Infections and infestations     
Bronchitis † 1  7/99 (7.07%)  11 8/98 (8.16%)  11
Herpes zoster † 1  9/99 (9.09%)  10 8/98 (8.16%)  8
Influenza † 1  5/99 (5.05%)  6 5/98 (5.10%)  5
Nasopharyngitis † 1  11/99 (11.11%)  18 14/98 (14.29%)  22
Sinusitis † 1  16/99 (16.16%)  28 17/98 (17.35%)  29
Upper respiratory tract infection † 1  29/99 (29.29%)  43 24/98 (24.49%)  40
Urinary tract infection † 1  18/99 (18.18%)  24 7/98 (7.14%)  10
Viral upper respiratory tract infection † 1  7/99 (7.07%)  8 4/98 (4.08%)  4
Investigations     
Alanine aminotransferase increased † 1  15/99 (15.15%)  23 22/98 (22.45%)  30
Aspartate aminotransferase increased † 1  11/99 (11.11%)  14 16/98 (16.33%)  21
Blood creatinine increased † 1  8/99 (8.08%)  10 10/98 (10.20%)  12
C-reactive protein increased † 1  8/99 (8.08%)  10 9/98 (9.18%)  11
Haematocrit decreased † 1  8/99 (8.08%)  8 16/98 (16.33%)  19
Haemoglobin decreased † 1  6/99 (6.06%)  7 7/98 (7.14%)  8
Red blood cell sedimentation rate increased † 1  5/99 (5.05%)  9 12/98 (12.24%)  14
Weight increased † 1  6/99 (6.06%)  8 8/98 (8.16%)  8
White blood cell count decreased † 1  6/99 (6.06%)  9 21/98 (21.43%)  43
Metabolism and nutrition disorders     
Hyperglycaemia † 1  12/99 (12.12%)  15 11/98 (11.22%)  11
Hyperkalaemia † 1  8/99 (8.08%)  19 5/98 (5.10%)  6
Hypokalaemia † 1  3/99 (3.03%)  4 7/98 (7.14%)  9
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  34/99 (34.34%)  42 24/98 (24.49%)  34
Back pain † 1  13/99 (13.13%)  13 10/98 (10.20%)  10
Joint swelling † 1  8/99 (8.08%)  9 3/98 (3.06%)  3
Muscle spasms † 1  20/99 (20.20%)  26 21/98 (21.43%)  23
Muscular weakness † 1  6/99 (6.06%)  7 4/98 (4.08%)  5
Musculoskeletal pain † 1  11/99 (11.11%)  11 4/98 (4.08%)  4
Myalgia † 1  5/99 (5.05%)  6 8/98 (8.16%)  8
Pain in extremity † 1  13/99 (13.13%)  17 10/98 (10.20%)  10
Nervous system disorders     
Dizziness † 1  14/99 (14.14%)  17 12/98 (12.24%)  16
Dysgeusia † 1  6/99 (6.06%)  7 6/98 (6.12%)  6
Headache † 1  28/99 (28.28%)  31 25/98 (25.51%)  41
Hypoaesthesia † 1  9/99 (9.09%)  10 8/98 (8.16%)  9
Paraesthesia † 1  4/99 (4.04%)  7 7/98 (7.14%)  9
Tremor † 1  10/99 (10.10%)  15 6/98 (6.12%)  6
Psychiatric disorders     
Depression † 1  7/99 (7.07%)  7 6/98 (6.12%)  6
Insomnia † 1  18/99 (18.18%)  20 14/98 (14.29%)  15
Renal and urinary disorders     
Haematuria † 1  6/99 (6.06%)  8 14/98 (14.29%)  16
Respiratory, thoracic and mediastinal disorders     
Cough † 1  32/99 (32.32%)  40 24/98 (24.49%)  31
Dysphonia † 1  10/99 (10.10%)  12 5/98 (5.10%)  7
Dyspnoea † 1  16/99 (16.16%)  18 15/98 (15.31%)  19
Epistaxis † 1  18/99 (18.18%)  26 15/98 (15.31%)  23
Haemoptysis † 1  8/99 (8.08%)  10 7/98 (7.14%)  8
Nasal congestion † 1  13/99 (13.13%)  13 8/98 (8.16%)  9
Oropharyngeal pain † 1  11/99 (11.11%)  14 3/98 (3.06%)  4
Paranasal sinus hypersecretion † 1  5/99 (5.05%)  7 6/98 (6.12%)  8
Productive cough † 1  7/99 (7.07%)  8 7/98 (7.14%)  11
Rhinorrhoea † 1  6/99 (6.06%)  6 5/98 (5.10%)  5
Skin and subcutaneous tissue disorders     
Acne † 1  7/99 (7.07%)  9 5/98 (5.10%)  5
Alopecia † 1  11/99 (11.11%)  13 21/98 (21.43%)  21
Rash † 1  14/99 (14.14%)  19 23/98 (23.47%)  28
Vascular disorders     
Flushing † 1  6/99 (6.06%)  11 7/98 (7.14%)  8
Hypertension † 1  14/99 (14.14%)  18 10/98 (10.20%)  10
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
[Not Specified]
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Associate Director, Clinical Research Program
Organization: DAIT/NIAID
Phone: (301) 594-7669
EMail: DAITClinicalTrialsGov@niaid.nih.gov
Publications of Results:
Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Fessler BJ, Ding L, Viviano L, Tchao NK, Phippard DJ, Asare AL, Lim N, Ikle D, Jepson B, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Mueller M, Sejismundo LP, Mieras K, Stone JH; RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug 1;369(5):417-27. doi: 10.1056/NEJMoa1213277.
Miloslavsky EM, Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Viviano L, Ding L, Sejismundo LP, Mieras K, Ikle D, Jepson B, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2013 Sep;65(9):2441-9. doi: 10.1002/art.38044.
Monach PA, Warner RL, Tomasson G, Specks U, Stone JH, Ding L, Fervenza FC, Fessler BJ, Hoffman GS, Ikle D, Kallenberg CG, Krischer J, Langford CA, Mueller M, Seo P, St Clair EW, Spiera R, Tchao N, Ytterberg SR, Johnson KJ, Merkel PA. Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. Ann Rheum Dis. 2013 Aug;72(8):1342-50. doi: 10.1136/annrheumdis-2012-201981. Epub 2012 Sep 12.
Nasrallah M, Pouliot Y, Hartmann B, Dunn P, Thomson E, Wiser J, Butte AJ. Reanalysis of the Rituximab in ANCA-Associated Vasculitis trial identifies granulocyte subsets as a novel early marker of successful treatment. Arthritis Res Ther. 2015 Sep 21;17(1):262. doi: 10.1186/s13075-015-0778-z.
Miloslavsky EM, Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Ding L, Ikle D, Villareal M, Lim N, Brunetta P, Fervenza FC, Monach PA, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids. Arthritis Rheumatol. 2015 Jun;67(6):1629-36. doi: 10.1002/art.39104.
Miloslavsky EM, Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Viviano L, Ding L, Ikle D, Villarreal M, Jepson B, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 2014 Nov;66(11):3151-9. doi: 10.1002/art.38788.
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00104299    
Other Study ID Numbers: DAIT ITN021AI
First Submitted: February 24, 2005
First Posted: February 25, 2005
Results First Submitted: February 2, 2011
Results First Posted: August 25, 2011
Last Update Posted: April 21, 2017