Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis - Full Text View

Sponsor:	National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators:	Immune Tolerance Network (ITN) Genentech
Information provided by:	National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:	NCT00104299

Purpose

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.

Condition	Intervention	Phase
Vasculitis Wegener's Granulomatosis Microscopic Polyangiitis	Drug: Rituximab plus cyclophosphamide placebo (rituximab group) Drug: Cyclophosphamide plus rituximab placebo (control group) Drug: Azathioprine Drug: Methylprednisolone (or other glucocorticoid) Drug: Prednisone	Phase II Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Rituximab Therapy for the Induction of Remission and Tolerance in ANCA-Associated Vasculitis (ITN021AI)

Resource links provided by NLM:

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:

Disease Remission [ Time Frame: 6 months post-randomization ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

Rate of Selected Adverse Events Experienced by Participants Receiving Rituximab Versus Those Receiving Conventional Therapy [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
Rate of 10 adverse events selected for their relationship to vasculitis and the treatments tested in this protocol

Enrollment:	197
Study Start Date:	January 2005
Study Completion Date:	January 2010
Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Rituximab	Drug: Rituximab plus cyclophosphamide placebo (rituximab group) 375 mg/m^2 infusions once weekly for 4 week Other Name: Rituxan 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
Active Comparator: Control Group	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

Arms

Assigned Interventions

Experimental: Rituximab

Drug: Rituximab plus cyclophosphamide placebo (rituximab group)

375 mg/m^2 infusions once weekly for 4 week

Other Name: Rituxan

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

Active Comparator: Control Group

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

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.

Eligibility

Ages Eligible for Study:	15 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00104299

Locations

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

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network (ITN)

Genentech

Investigators

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

More Information

Additional Information:

Click here for the Immune Tolerance Network Web site This link exits the ClinicalTrials.gov site

Publications:

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.

Responsible Party:	Associate Director, Clinical Research Program, DAIT/NIAID
ClinicalTrials.gov Identifier:	NCT00104299 History of Changes
Other Study ID Numbers:	DAIT ITN021AI
Study First Received:	February 24, 2005
Results First Received:	February 2, 2011
Last Updated:	July 27, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

ANCA
Vasculitis
Wegener's Granulomatosis
microscopic polyangiitis

ANCA-positive
ANCA-associated
ANCA-associated vasculitis
MPA

Additional relevant MeSH terms:

Vasculitis
Wegener Granulomatosis
Systemic Vasculitis
Microscopic Polyangiitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Autoimmune Diseases
Immune System Diseases
Azathioprine
Cyclophosphamide
Rituximab

Methylprednisolone Hemisuccinate
Prednisolone
Prednisone
Glucocorticoids
Methylprednisolone
Prednisolone phosphate
Methylprednisolone acetate
Prednisolone acetate
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents

ClinicalTrials.gov processed this record on February 12, 2012