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

Sponsors and Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) Immune Tolerance Network
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 adults 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 Granulomatosis	Drug: Rituximab Drug: Cyclophosphamide Drug: Azathioprine Drug: Methylprednisolone (or other glucocorticoid) Drug: Prednisone	Phase II Phase III

MedlinePlus related topics: Vasculitis Wegener's Granulomatosis

Drug Information available for: Cyclophosphamide Prednisolone Prednisolone acetate Prednisone Depo-medrol Azathioprine sodium salt Medrol veriderm Methylprednisolone Rituximab Prednisolone sodium phosphate Azathioprine Prednisolone Sodium Succinate Methylprednisolone Sodium Succinate Methylprednisolone hemisuccinate 6-Methylprednisolone

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study
Official Title:	Rituximab Therapy for the Induction of Remission and Tolerance in ANCA-Associated Vasculitis

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

Primary Outcome Measures:

Ability of rituximab to induce complete remission during the first 6 months after randomization [ Time Frame: 6 months ] [ Designated as safety issue: No ]

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 ]

Estimated Enrollment:	200
Study Start Date:	January 2005
Estimated Study Completion Date:	March 2010
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	Drug: Rituximab 375 mg/m2 infusions once weekly for 4 week Drug: Methylprednisolone (or other glucocorticoid) 1 g/day IV for up to 3 days within 14 days prior to receiving rituximab 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.
2: Active Comparator	Drug: Cyclophosphamide 2 mg/kg/day orally for months 1-3 Drug: Azathioprine 2 mg/kg/day orally for months 4-6 Drug: Methylprednisolone (or other glucocorticoid) 1 g/day IV for up to 3 days within 14 days prior to receiving rituximab 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.

Arms

Assigned Interventions

1: Experimental

Drug: Rituximab

375 mg/m2 infusions once weekly for 4 week

Drug: Methylprednisolone (or other glucocorticoid)

1 g/day IV for up to 3 days within 14 days prior to receiving rituximab

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.

2: Active Comparator

Drug: Cyclophosphamide

2 mg/kg/day orally for months 1-3

Drug: Azathioprine

2 mg/kg/day orally for months 4-6

Drug: Methylprednisolone (or other glucocorticoid)

1 g/day IV for up to 3 days within 14 days prior to receiving rituximab

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.

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 adults 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 IV 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 IV 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/m2) 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 the remission induction phase 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 lbs (40 kg)
Diagnosis of Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) according to the definitions of the Chapel Hill Consensus Conference
Newly diagnosed patient of WG or MPA 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 or MPO-ANCA 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 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

Investigators

Principal Investigator:	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

No publications provided

Responsible Party:	DAIT/NIAID ( Associate Director, Clinical Research Program )
Study ID Numbers:	ITN021AI
Study First Received:	February 24, 2005
Last Updated:	March 26, 2009
ClinicalTrials.gov Identifier:	NCT00104299 History of Changes
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

Study placed in the following topic categories:

Anti-Inflammatory Agents
Antimetabolites
Prednisone
Immunologic Factors
Methylprednisolone
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Prednisolone acetate
Cyclophosphamide
Neuroprotective Agents
Hormones
Azathioprine
Urologic Diseases
Respiratory Tract Diseases

Wegener's Granulomatosis
Kidney Diseases
Alkylating Agents
Methylprednisolone Hemisuccinate
Lung Diseases, Interstitial
Vasculitis
Antineoplastic Agents, Hormonal
Rituximab
Vascular Diseases
Methylprednisolone acetate
Glucocorticoids
Immunosuppressive Agents
Microscopic Polyangiitis
Wegener Granulomatosis
Lung Diseases

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Antimetabolites
Prednisone
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Methylprednisolone
Antineoplastic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Prednisolone acetate
Cyclophosphamide
Neuroprotective Agents
Hormones

Azathioprine
Urologic Diseases
Respiratory Tract Diseases
Therapeutic Uses
Cardiovascular Diseases
Kidney Diseases
Alkylating Agents
Methylprednisolone Hemisuccinate
Lung Diseases, Interstitial
Vasculitis
Antineoplastic Agents, Hormonal
Rituximab
Gastrointestinal Agents
Vascular Diseases
Methylprednisolone acetate

ClinicalTrials.gov processed this record on May 07, 2009