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

Vasculitis Clinical Trial

— RAVE  

Official title:

Rituximab Therapy for the Induction of Remission and Tolerance in ANCA-Associated Vasculitis (ITN021AI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00104299
• Other study ID #: DAIT ITN021AI
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: February 24, 2005
• Last updated: October 17, 2013
• Start date: January 2005
• Est. completion date: January 2010

Study information

• Verified date: October 2013
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 197
• Est. completion date: January 2010
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
• Microscopic Polyangiitis
• Systemic Vasculitis
• Vasculitis
• Wegener Granulomatosis
• Wegener's Granulomatosis

Intervention

Drug:
• Rituximab plus cyclophosphamide placebo (rituximab group)
375 mg/m^2 infusions once weekly for 4 week
• Cyclophosphamide plus rituximab placebo (control group)
2 mg/kg/day orally for months 1-3
• Azathioprine
2 mg/kg/day orally for months 4-6
• Methylprednisolone (or other glucocorticoid)
1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab
• 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.

Locations

Country	Name	City	State
Netherlands	University Hospital Groningen	Groningen
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	Boston University	Boston	Massachusetts
United States	The Cleveland Clinic	Cleveland	Ohio
United States	Duke University	Durham	North Carolina
United States	Hospital for Special Surgery	New York	New York
United States	Mayo Clinic Foundation	Rochester	Minnesota

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Genentech, Inc., Immune Tolerance Network (ITN)

Countries where clinical trial is conducted

United States,  Netherlands, 

References & Publications (5)

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, Iklé D, Jepson B, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, — View Citation

Monach PA, Warner RL, Tomasson G, Specks U, Stone JH, Ding L, Fervenza FC, Fessler BJ, Hoffman GS, Iklé 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 reflec — View Citation

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, — View Citation

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 — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Remission	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.	6 months post-randomization	No
Secondary	Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy	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	Through common close-out (defined as 18 months after the last participant is enrolled in the trial)	Yes
Secondary	Percentage of Participants Who Have a BVAS/WG Score of 0 and Have Successfully Completed the Glucocorticoid Taper by 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	6 months post-randomization	No
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	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	18 months post-randomization	No
Secondary	The Duration of Remission (BVAS=0), the Time to Limited and/or Severe Flare After Remission in the Two Treatment Groups	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.	18 months post-randomization	No
Secondary	Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups	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	18 months post-randomization	No
Secondary	Time to Complete Remission (BVAS=0, Off Glucocorticoids) From the Visit 1 Baseline Visit in the Two Treatment Groups	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	18 months post-randomization	No

External Links

•   Click here for the Immune Tolerance Network Web site
•   Immune Tolerance Network (ITN) TrialShare: open public access to participant-level data available for this trial