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

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

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Eight centers in the United States and one center in the Netherlands (Groningen) enrolled 197 Antineutrophil cytoplasmic antibodies (ANCA)-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis between December 30, 2004 and June 30, 2008.

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

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

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



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

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

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



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

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
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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.

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.

Serious Adverse Events
    Rituximab     Control Group  
Total, serious adverse events      
# participants affected / at risk     60/99 (60.61%)     47/98 (47.96%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     3/99 (3.03%)     4/98 (4.08%)  
# events     3     6  
Autoimmune thrombocytopenia † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Febrile neutropenia † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Leukopenia † 1    
# participants affected / at risk     3/99 (3.03%)     0/98 (0.00%)  
# events     5     0  
Pancytopenia † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Cardiac disorders      
Atrial fibrillation † 1    
# participants affected / at risk     2/99 (2.02%)     0/98 (0.00%)  
# events     2     0  
Atrial tachycardia † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Myocardial infarction † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Supraventricular tachycardia † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Ear and labyrinth disorders      
Sudden hearing loss † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Eye disorders      
Keratitis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Ulcerative keratitis † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Gastrointestinal disorders      
Colitis ischaemic † 1    
# participants affected / at risk     2/99 (2.02%)     0/98 (0.00%)  
# events     2     0  
Diarrhoea † 1    
# participants affected / at risk     2/99 (2.02%)     0/98 (0.00%)  
# events     2     0  
Gastritis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Impaired gastric emptying † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pancreatitis acute † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Upper gastrointestinal haemorrhage † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
General disorders      
Adverse drug reaction † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Asthenia † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Chest pain † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Chills † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Multi-organ failure † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pyrexia † 1    
# participants affected / at risk     2/99 (2.02%)     0/98 (0.00%)  
# events     2     0  
Hepatobiliary disorders      
Cholelithiasis † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Immune system disorders      
Anti-neutrophil cytoplasmic antibody positive vasculitis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Drug hypersensitivity † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Hypersensitivity † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Infections and infestations      
Abdominal abscess † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Abscess limb † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Acute sinusitis † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Bronchitis † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Cellulitis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Cellulitis orbital † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Cellulitis staphylococcal † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Central line infection † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Clostridial infection † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     2     0  
Clostridium difficile colitis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Escherichia infection † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Gastroenteritis viral † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Infective exacerbation of chronic obstructive airways disease † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Influenza † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Lobar pneumonia † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Osteomyelitis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Periorbital cellulitis † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     2  
Pneumocystis jiroveci pneumonia † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Pneumonia † 1    
# participants affected / at risk     8/99 (8.08%)     10/98 (10.20%)  
# events     10     11  
Pneumonia bacterial † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Post streptococcal glomerulonephritis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Respiratory tract infection † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Sepsis † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Septic shock † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Skin infection † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Upper respiratory tract infection † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Urinary tract infection † 1    
# participants affected / at risk     2/99 (2.02%)     1/98 (1.02%)  
# events     2     1  
Viral upper respiratory tract infection † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Injury, poisoning and procedural complications      
Accidental overdose † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Clavicle fracture † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Fall † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pelvic fracture † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Subdural haematoma † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Investigations      
Blood creatinine increased † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
C-reactive protein increased † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Haemoglobin decreased † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Metabolism and nutrition disorders      
Dehydration † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Gout † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Hypercalcaemia † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     2  
Hypovolaemia † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Type 2 diabetes mellitus † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Musculoskeletal and connective tissue disorders      
Bone disorder † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Intervertebral disc protrusion † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Osteoarthritis † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     2     1  
Osteonecrosis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Spinal column stenosis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Bladder transitional cell carcinoma † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Colon cancer † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Colon cancer metastatic † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Lung neoplasm malignant † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Prostate cancer † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Squamous cell carcinoma of skin † 1    
# participants affected / at risk     0/99 (0.00%)     2/98 (2.04%)  
# events     0     6  
Thyroid cancer † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Uterine cancer † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Nervous system disorders      
Cerebrovascular accident † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Haemorrhagic stroke † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Somnolence † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Syncope † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pregnancy, puerperium and perinatal conditions      
Abortion spontaneous † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pregnancy † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Psychiatric disorders      
Depression † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Suicidal ideation † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Suicide attempt † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Renal and urinary disorders      
Acute prerenal failure † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Bladder disorder † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Nephrolithiasis † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Renal failure † 1    
# participants affected / at risk     4/99 (4.04%)     2/98 (2.04%)  
# events     4     2  
Renal failure acute † 1    
# participants affected / at risk     2/99 (2.02%)     3/98 (3.06%)  
# events     2     3  
Renal failure chronic † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Urinary incontinence † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Reproductive system and breast disorders      
Endometriosis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Respiratory, thoracic and mediastinal disorders      
Acute respiratory distress syndrome † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Chronic obstructive pulmonary disease † 1    
# participants affected / at risk     0/99 (0.00%)     1/98 (1.02%)  
# events     0     1  
Dyspnoea † 1    
# participants affected / at risk     2/99 (2.02%)     0/98 (0.00%)  
# events     2     0  
Interstitial lung disease † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Laryngeal stenosis † 1    
# participants affected / at risk     2/99 (2.02%)     2/98 (2.04%)  
# events     2     3  
Lung infiltration † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Pulmonary alveolar haemorrhage † 1    
# participants affected / at risk     2/99 (2.02%)     2/98 (2.04%)  
# events     2     2  
Pulmonary embolism † 1    
# participants affected / at risk     3/99 (3.03%)     2/98 (2.04%)  
# events     3     2  
Pulmonary haemorrhage † 1    
# participants affected / at risk     1/99 (1.01%)     1/98 (1.02%)  
# events     1     1  
Wegener's granulomatosis † 1    
# participants affected / at risk     8/99 (8.08%)     4/98 (4.08%)  
# events     9     5  
Vascular disorders      
Aortic dissection † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Deep vein thrombosis † 1    
# participants affected / at risk     1/99 (1.01%)     8/98 (8.16%)  
# events     1     8  
Peripheral arterial occlusive disease † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Thrombosis † 1    
# participants affected / at risk     1/99 (1.01%)     0/98 (0.00%)  
# events     1     0  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 11.1




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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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