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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: March 23, 2017
Last verified: March 2017
Results First Received: February 2, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: 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

  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 
Overall Participants Analyzed 
[Units: Participants]
 99   98   197 
Age 
[Units: Participants]
Count of 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 
[Units: Years]
Mean (Standard Deviation)
 54.0  (16.8)   51.5  (14.1)   52.8  (15.5) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      52  52.5%      45  45.9%      97  49.2% 
Male      47  47.5%      53  54.1%      100  50.8% 
Region of Enrollment 
[Units: Participants]
     
United States   91   90   181 
Netherlands   8   8   16 
BVAS/WG [1] 
[Units: Score units]
Mean (Standard Deviation)
 8.1  (2.8)   8.0  (3.4)   8.0  (3.1) 
[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.
VDI [1] 
[Units: Score units]
Mean (Standard Deviation)
 1.4  (1.8)   1.0  (1.4)   1.2  (1.7) 
[1] 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%)   97/98 (98.98%) 
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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