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

• 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: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN); Genentech, Inc.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: February 24, 2005
• First Posted Date: February 25, 2005
• Results First Submitted Date: February 2, 2011
• Results First Posted Date: August 25, 2011
• Last Update Posted Date: April 21, 2017
• Study Start Date: January 2005
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 27, 2011)

Disease Remission [ Time Frame: 6 months post-randomization ]

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.

• Original Primary Outcome Measures (submitted: June 23, 2005): Ability of rituximab to induce complete remission during the first 6 months after randomization

Current Secondary Outcome Measures (submitted: April 12, 2013)

• 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) ]
  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
• 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 ]
  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
• 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 ]
  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
• 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 ]
  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 to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups [ Time Frame: 18 months post-randomization ]
  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 to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups [ Time Frame: 18 months post-randomization ]
  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

• Original Secondary Outcome Measures (submitted: June 23, 2005): Rate of selected adverse events experienced by participants receiving rituximab versus those receiving conventional therapy
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis
• Official Title: Rituximab Therapy for the Induction of Remission and Tolerance in ANCA-Associated Vasculitis (ITN021AI)

Brief Summary

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is the most common type of small blood vessel inflammation in adults. ANCA-associated vasculitis includes Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Rituximab is a man-made antibody used to treat certain types of cancer. The purpose of this study is to determine the effectiveness of rituximab in treating patients with WG and MPA.

Study hypothesis: Rituximab is not inferior to conventional therapy in its ability to induce disease remission by Month 6.

Detailed Description

Current conventional therapies for ANCA-associated vasculitis (AAV) are associated with high incidences of treatment failure, disease relapse, substantial toxicity, and patient morbidity and mortality. Rituximab is a monoclonal antibody used to treat non-Hodgkin's lymphoma. This study will evaluate the efficacy of rituximab with glucocorticoids in inducing disease remission in patients with severe forms of AAV (WG and MPA).

The study consists of two phases: a 6-month remission induction phase, followed by a 12-month remission maintenance phase. All participants will receive at least 1 g of pulse intravenous methylprednisolone or a dose-equivalent of another glucocorticoid preparation. Depending on the participant's condition, he or she may receive up to 3 days of intravenous methylprednisolone for a total of 3 g of methylprednisolone (or a dose-equivalent). During the remission induction phase, all participants will receive oral prednisone daily (1 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6 study visit.

Next, participants will be randomly assigned to one of two arms. Arm 1 participants will receive rituximab (375 mg/m^2) infusions once weekly for 4 weeks and cyclophosphamide (CYC) placebo daily for 3 to 6 months. Arm 2 participants will receive rituximab placebo infusions once weekly for 4 weeks and CYC daily for 3 to 6 months. During the remission maintenance phase, participants in Arm 1 will discontinue CYC placebo and start oral azathioprine (AZA) placebo daily until Month 18. Participants in Arm 2 will discontinue CYC and start AZA daily until Month 18. Participants who fail treatment before Month 6 will be crossed over to the other treatment arm unless there are specific contraindications. Participants in either group who reach clinical remission before they complete 6 months of therapy may switch from CYC/placebo to AZA/placebo if directed by their physicians.

All participants will be followed for at least 18 months. Initially, study visits are weekly, progressing to monthly and then quarterly visits as the study proceeds. Blood collection will occur at each study visit.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Vasculitis
• Wegener's Granulomatosis
• Microscopic Polyangiitis

Intervention

• Drug: Rituximab plus cyclophosphamide placebo (rituximab group)
  375 mg/m^2 infusions once weekly for 4 week
  Other Name: Rituxan
• Drug: Cyclophosphamide plus rituximab placebo (control group)
  2 mg/kg/day orally for months 1-3
  Other Name: Cytoxan
• Drug: Azathioprine
  2 mg/kg/day orally for months 4-6
  Other Name: imuran
• Drug: Methylprednisolone (or other glucocorticoid)
  1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab
  Other Name: Medrol
• Drug: Prednisone
  During the remission induction phase, all participants will receive oral prednisone daily (1 mg/kg/day, not to exceed 80 mg/day). Prednisone tapering will be completed by the Month 6 study visit.
  Other Name: Deltasone, Liquid Pred, Meticorten, Orasone

Study Arms

• Experimental: Rituximab
  Interventions:

  • Drug: Rituximab plus cyclophosphamide placebo (rituximab group)
  • Drug: Methylprednisolone (or other glucocorticoid)
  • Drug: Prednisone
• Active Comparator: Control Group
  Interventions:

  • Drug: Cyclophosphamide plus rituximab placebo (control group)
  • Drug: Azathioprine
  • Drug: Methylprednisolone (or other glucocorticoid)
  • Drug: Prednisone

Publications *

• Zarin DA. Participant-level data and the new frontier in trial transparency. N Engl J Med. 2013 Aug 1;369(5):468-9. doi: 10.1056/NEJMe1307268. No abstract available.
• 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.
• Berti A, Hillion S, Hummel AM, Son YM, Chriti N, Peikert T, Carmona EM, Abdulahad WH, Heeringa P, Harris KM, St Clair EW, Brunetta P, Fervenza FC, Langford CA, Kallenberg CG, Merkel PA, Monach PA, Seo P, Spiera RF, Stone JH, Grandi G, Sun J, Pers JO, Specks U, Cornec D; RAVE-ITN Research Group. Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis. JCI Insight. 2021 Nov 22;6(22):e150999. doi: 10.1172/jci.insight.150999.
• Kronbichler A, Leierer J, Shin JI, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CGM, St Clair EW, Brunetta P, Fervenza FC, Geetha D, Keogh KA, Monach PA, Ytterberg SR, Mayer G, Specks U, Stone JH; RAVE-ITN Research Group. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2019 Nov;71(11):1888-1893. doi: 10.1002/art.41017. Epub 2019 Sep 25.
• Wallace ZS, Miloslavsky EM, Cascino M, Unizony SH, Lu N, Hoffman GS, Kallenberg CGM, Langford CA, Merkel PA, Monach PA, Seo P, Spiera R, St Clair EW, Specks U, Brunetta P, Choi HK, Stone JH. Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care Res (Hoboken). 2017 Jul;69(7):1004-1010. doi: 10.1002/acr.23099.
• Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CM, St Clair EW, Ikle D, Tchao NK, Ding L, Brunetta P, Choi HK, Monach PA, Fervenza F, Stone JH, Specks U; RAVE-ITN Research Group. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016 Jun;75(6):1166-9. doi: 10.1136/annrheumdis-2015-208073. Epub 2015 Nov 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 27, 2011): 197
• Original Enrollment (submitted: June 23, 2005): 200
• Actual Study Completion Date: January 2010
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Weight of at least 88 pounds(40 kilograms)
• Diagnosis of Wegener's granulomatosis or microscopic polyangiitis according to the definitions of the Chapel Hill Consensus Conference
• Newly diagnosed patient of Wegener's granulomatosis or microscopic polyangiitis OR must be experiencing a disease flare characterized by: (a) active disease with a Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG) of 3 or greater that would normally require treatment with CYC; OR (b) disease severe enough to require treatment with CYC; OR (c) must be positive for either PR3-ANCA (ANCA directed against proteinase 3) or MPO-ANCA (ANCA directed against myeloperoxidase)at the screening
• Willing to use acceptable forms of contraception for the duration of the study and for up to 1 year after stopping study medications
• Willing to report pregnancies (female participants or male participants' partners) occurring at any time during the study and for up to 1 year after stopping study medications
• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Diagnosis of Churg-Strauss Syndrome according to the definitions of the Chapel Hill Consensus Conference
• Have limited disease that would not normally be treated with CYC
• Requires mechanical ventilation because of alveolar hemorrhage
• History of severe allergic reactions to human or chimeric monoclonal antibodies
• Active systemic infection
• Have a deep-space infection, such as osteomyelitis, septic arthritis, or pneumonia complicated by pleural cavity or lung abscess, within 6 months prior to study entry
• History of or current hepatitis B or C infection
• HIV (human immunodeficiency virus) infected
• Acute or chronic liver disease that, in the opinion of the investigator, may interfere with the study
• History of or active cancer diagnosed within the last 5 years. Individuals with squamous cell or basal cell carcinomas of the skin and individuals with cervical carcinoma in situ who have received curative surgical treatment may be eligible for this study.
• History of anti-glomerular basement membrane (anti-GBM) disease
• Other uncontrolled disease, including drug and alcohol abuse, that may interfere with the study
• Pregnancy or breastfeeding

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands, United States

Administrative Information

• NCT Number: NCT00104299
• Other Study ID Numbers: DAIT ITN021AI
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Participant level data and additional relevant materials are available to the public in: 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts; and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal.

• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Not Provided
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current

Collaborators

• Immune Tolerance Network (ITN)
• Genentech, Inc.

Investigators

• Study Chair: John H. Stone, MD, MPH; Johns Hopkins University
• Study Chair: Ulrich Specks, MD; Mayo Clinic

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: March 2017