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

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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 Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Disease Remission

Secondary Outcome

 Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy

Condition

Vasculitis

Intervention

Rituximab plus cyclophosphamide placebo (rituximab group)

Study Arms / Comparison Groups

 Rituximab
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

197

Start Date

January 2005

Completion Date

January 2010

Primary Completion Date

December 2008

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
      

Gender

All

Ages

15 Years - N/A

Accepts Healthy Volunteers

No

Contacts

John H. Stone, MD, MPH, , 

Location Countries

Netherlands

Location Countries

Netherlands

Administrative Informations


NCT ID

NCT00104299

Organization ID

DAIT ITN021AI


Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

 Immune Tolerance Network (ITN)

Study Sponsor

John H. Stone, MD, MPH, Study Chair, Johns Hopkins University


Verification Date

March 2017