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.
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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 ]

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
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Time Frame From randomization through common close out (defined as 18 months after the last participant is enrolled in the trial)
Additional 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.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

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.

Other Adverse Events
    Rituximab     Control Group  
Total, other (not including serious) adverse events      
# participants affected / at risk     97/99     97/98  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     22/99 (22.22%)     18/98 (18.37%)  
# events     28     23  
Leukopenia † 1    
# participants affected / at risk     13/99 (13.13%)     39/98 (39.80%)  
# events     30     80  
Thrombocytopenia † 1    
# participants affected / at risk     9/99 (9.09%)     5/98 (5.10%)  
# events     13     6  
Ear and labyrinth disorders      
Ear pain † 1    
# participants affected / at risk     7/99 (7.07%)     5/98 (5.10%)  
# events     8     5  
Endocrine disorders      
Cushingoid † 1    
# participants affected / at risk     5/99 (5.05%)     6/98 (6.12%)  
# events     6     6  
Eye disorders      
Vision blurred † 1    
# participants affected / at risk     4/99 (4.04%)     7/98 (7.14%)  
# events     4     7  
Gastrointestinal disorders      
Diarrhoea † 1    
# participants affected / at risk     27/99 (27.27%)     20/98 (20.41%)  
# events     35     25  
Dyspepsia † 1    
# participants affected / at risk     7/99 (7.07%)     8/98 (8.16%)  
# events     7     8  
Gastrooesophageal reflux disease † 1    
# participants affected / at risk     10/99 (10.10%)     6/98 (6.12%)  
# events     10     6  
Nausea † 1    
# participants affected / at risk     25/99 (25.25%)     31/98 (31.63%)  
# events     28     41  
Vomiting † 1    
# participants affected / at risk     8/99 (8.08%)     13/98 (13.27%)  
# events     12     18  
General disorders      
Chest discomfort † 1    
# participants affected / at risk     6/99 (6.06%)     4/98 (4.08%)  
# events     7     4  
Chest pain † 1    
# participants affected / at risk     6/99 (6.06%)     4/98 (4.08%)  
# events     6     4  
Chills † 1    
# participants affected / at risk     6/99 (6.06%)     5/98 (5.10%)  
# events     7     5  
Fatigue † 1    
# participants affected / at risk     26/99 (26.26%)     30/98 (30.61%)  
# events     32     42  
Oedema peripheral † 1    
# participants affected / at risk     22/99 (22.22%)     14/98 (14.29%)  
# events     26     19  
Pyrexia † 1    
# participants affected / at risk     10/99 (10.10%)     17/98 (17.35%)  
# events     12     25  
Infections and infestations      
Bronchitis † 1    
# participants affected / at risk     7/99 (7.07%)     8/98 (8.16%)  
# events     11     11  
Herpes zoster † 1    
# participants affected / at risk     9/99 (9.09%)     8/98 (8.16%)  
# events     10     8  
Influenza † 1    
# participants affected / at risk     5/99 (5.05%)     5/98 (5.10%)  
# events     6     5  
Nasopharyngitis † 1    
# participants affected / at risk     11/99 (11.11%)     14/98 (14.29%)  
# events     18     22  
Sinusitis † 1    
# participants affected / at risk     16/99 (16.16%)     17/98 (17.35%)  
# events     28     29  
Upper respiratory tract infection † 1    
# participants affected / at risk     29/99 (29.29%)     24/98 (24.49%)  
# events     43     40  
Urinary tract infection † 1    
# participants affected / at risk     18/99 (18.18%)     7/98 (7.14%)  
# events     24     10  
Viral upper respiratory tract infection † 1    
# participants affected / at risk     7/99 (7.07%)     4/98 (4.08%)  
# events     8     4  
Investigations      
Alanine aminotransferase increased † 1    
# participants affected / at risk     15/99 (15.15%)     22/98 (22.45%)  
# events     23     30  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     11/99 (11.11%)     16/98 (16.33%)  
# events     14     21  
Blood creatinine increased † 1    
# participants affected / at risk     8/99 (8.08%)     10/98 (10.20%)  
# events     10     12  
C-reactive protein increased † 1    
# participants affected / at risk     8/99 (8.08%)     9/98 (9.18%)  
# events     10     11  
Haematocrit decreased † 1    
# participants affected / at risk     8/99 (8.08%)     16/98 (16.33%)  
# events     8     19  
Haemoglobin decreased † 1    
# participants affected / at risk     6/99 (6.06%)     7/98 (7.14%)  
# events     7     8  
Red blood cell sedimentation rate increased † 1    
# participants affected / at risk     5/99 (5.05%)     12/98 (12.24%)  
# events     9     14  
Weight increased † 1    
# participants affected / at risk     6/99 (6.06%)     8/98 (8.16%)  
# events     8     8  
White blood cell count decreased † 1    
# participants affected / at risk     6/99 (6.06%)     21/98 (21.43%)  
# events     9     43  
Metabolism and nutrition disorders      
Hyperglycaemia † 1    
# participants affected / at risk     12/99 (12.12%)     11/98 (11.22%)  
# events     15     11  
Hyperkalaemia † 1    
# participants affected / at risk     8/99 (8.08%)     5/98 (5.10%)  
# events     19     6  
Hypokalaemia † 1    
# participants affected / at risk     3/99 (3.03%)     7/98 (7.14%)  
# events     4     9  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     34/99 (34.34%)     24/98 (24.49%)  
# events     42     34  
Back pain † 1    
# participants affected / at risk     13/99 (13.13%)     10/98 (10.20%)  
# events     13     10  
Joint swelling † 1    
# participants affected / at risk     8/99 (8.08%)     3/98 (3.06%)  
# events     9     3  
Muscle spasms † 1    
# participants affected / at risk     20/99 (20.20%)     21/98 (21.43%)  
# events     26     23  
Muscular weakness † 1    
# participants affected / at risk     6/99 (6.06%)     4/98 (4.08%)  
# events     7     5  
Musculoskeletal pain † 1    
# participants affected / at risk     11/99 (11.11%)     4/98 (4.08%)  
# events     11     4  
Myalgia † 1    
# participants affected / at risk     5/99 (5.05%)     8/98 (8.16%)  
# events     6     8  
Pain in extremity † 1    
# participants affected / at risk     13/99 (13.13%)     10/98 (10.20%)  
# events     17     10  
Nervous system disorders      
Dizziness † 1    
# participants affected / at risk     14/99 (14.14%)     12/98 (12.24%)  
# events     17     16  
Dysgeusia † 1    
# participants affected / at risk     6/99 (6.06%)     6/98 (6.12%)  
# events     7     6  
Headache † 1    
# participants affected / at risk     28/99 (28.28%)     25/98 (25.51%)  
# events     31     41  
Hypoaesthesia † 1    
# participants affected / at risk     9/99 (9.09%)     8/98 (8.16%)  
# events     10     9  
Paraesthesia † 1    
# participants affected / at risk     4/99 (4.04%)     7/98 (7.14%)  
# events     7     9  
Tremor † 1    
# participants affected / at risk     10/99 (10.10%)     6/98 (6.12%)  
# events     15     6  
Psychiatric disorders      
Depression † 1    
# participants affected / at risk     7/99 (7.07%)     6/98 (6.12%)  
# events     7     6  
Insomnia † 1    
# participants affected / at risk     18/99 (18.18%)     14/98 (14.29%)  
# events     20     15  
Renal and urinary disorders      
Haematuria † 1    
# participants affected / at risk     6/99 (6.06%)     14/98 (14.29%)  
# events     8     16  
Respiratory, thoracic and mediastinal disorders      
Cough † 1    
# participants affected / at risk     32/99 (32.32%)     24/98 (24.49%)  
# events     40     31  
Dysphonia † 1    
# participants affected / at risk     10/99 (10.10%)     5/98 (5.10%)  
# events     12     7  
Dyspnoea † 1    
# participants affected / at risk     16/99 (16.16%)     15/98 (15.31%)  
# events     18     19  
Epistaxis † 1    
# participants affected / at risk     18/99 (18.18%)     15/98 (15.31%)  
# events     26     23  
Haemoptysis † 1    
# participants affected / at risk     8/99 (8.08%)     7/98 (7.14%)  
# events     10     8  
Nasal congestion † 1    
# participants affected / at risk     13/99 (13.13%)     8/98 (8.16%)  
# events     13     9  
Oropharyngeal pain † 1    
# participants affected / at risk     11/99 (11.11%)     3/98 (3.06%)  
# events     14     4  
Paranasal sinus hypersecretion † 1    
# participants affected / at risk     5/99 (5.05%)     6/98 (6.12%)  
# events     7     8  
Productive cough † 1    
# participants affected / at risk     7/99 (7.07%)     7/98 (7.14%)  
# events     8     11  
Rhinorrhoea † 1    
# participants affected / at risk     6/99 (6.06%)     5/98 (5.10%)  
# events     6     5  
Skin and subcutaneous tissue disorders      
Acne † 1    
# participants affected / at risk     7/99 (7.07%)     5/98 (5.10%)  
# events     9     5  
Alopecia † 1    
# participants affected / at risk     11/99 (11.11%)     21/98 (21.43%)  
# events     13     21  
Rash † 1    
# participants affected / at risk     14/99 (14.14%)     23/98 (23.47%)  
# events     19     28  
Vascular disorders      
Flushing † 1    
# participants affected / at risk     6/99 (6.06%)     7/98 (7.14%)  
# events     11     8  
Hypertension † 1    
# participants affected / at risk     14/99 (14.14%)     10/98 (10.20%)  
# events     18     10  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 11.1



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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