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

March 23, 2017 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

197

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • University Hospital Groningen
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama
    • Maryland
      • Baltimore, Maryland, United States, 21224
        • Johns Hopkins University
    • Massachusetts
      • Boston, Massachusetts, United States, 02118
        • Boston University
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Foundation
    • New York
      • New York, New York, United States, 10128
        • Hospital for Special Surgery
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • The Cleveland Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

15 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control Group
Drug: Methylprednisolone (or other glucocorticoid)
1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab
Other Names:
  • 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 Names:
  • Deltasone, Liquid Pred, Meticorten, Orasone
Drug: Cyclophosphamide plus rituximab placebo (control group)
2 mg/kg/day orally for months 1-3
Other Names:
  • Cytoxan
Drug: Azathioprine
2 mg/kg/day orally for months 4-6
Other Names:
  • imuran
Experimental: Rituximab
Drug: Rituximab plus cyclophosphamide placebo (rituximab group)
375 mg/m^2 infusions once weekly for 4 week
Other Names:
  • Rituxan
Drug: Methylprednisolone (or other glucocorticoid)
1 g/day intravenously for up to 3 days within 14 days prior to receiving rituximab
Other Names:
  • 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 Names:
  • Deltasone, Liquid Pred, Meticorten, Orasone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
6 months post-randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Through common close-out (defined as 18 months after the last participant is enrolled in the trial)
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
6 months post-randomization
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
18 months post-randomization
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.
18 months post-randomization
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
18 months post-randomization
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
18 months post-randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Genentech, Inc.
Immune Tolerance Network (ITN)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Primary Completion (Actual)

December 1, 2008

Study Completion (Actual)

January 1, 2010

Study Registration Dates

First Submitted

February 24, 2005

First Submitted That Met QC Criteria

February 24, 2005

First Posted (Estimate)

February 25, 2005

Study Record Updates

Last Update Posted (Actual)

April 21, 2017

Last Update Submitted That Met QC Criteria

March 23, 2017

Last Verified

March 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DAIT ITN021AI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD 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.

Study Data/Documents

  1. Individual Participant Data Set
    Information identifier: SDY91
    Information comments: ImmPort study identifier is SDY91.
  2. Study summary, -design, -adverse event(s), -summary of participant assessments, -interventions, -medications, -demographics, -lab tests, -mechanistic assays, -files et al.
    Information identifier: SDY91
    Information comments: ImmPort study identifier is SDY91.
  3. Individual Participant Data Set
    Information identifier: ITN021AI
    Information comments: TrialShare study ID is ITN021AI.
  4. Study overview, -data and reports, -participant list, -manuscripts and abstracts, -availability of biospecimens.
    Information identifier: ITN021AI
    Information comments: TrialShare study ID is ITN021AI.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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