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

NCT00104299 | Completed Phase 2 Results DMC

• 1 other identifier: DAIT ITN021AI
• Study Type: interventional
• Target: 197
• Locations: 2 countries
• Sites: 8

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.

Conditions

Vasculitis; Wegener's Granulomatosis; Microscopic Polyangiitis

Keywords

ANCA; Vasculitis; Wegener's Granulomatosis; microscopic polyangiitis; ANCA-positive; ANCA-associated; ANCA-associated vasculitis; MPA

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (6)

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

  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

  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

  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

  18 months post-randomization

• Time to Remission (BVAS=0) From the Visit 1 Baseline Visit in the Two Treatment Groups

  18 months post-randomization

Study Arms (2)

Rituximab

EXPERIMENTAL

Drug: Rituximab plus cyclophosphamide placebo (rituximab group); Drug: Methylprednisolone (or other glucocorticoid); Drug: Prednisone

Control Group

ACTIVE COMPARATOR

Drug: Cyclophosphamide plus rituximab placebo (control group); Drug: Azathioprine; Drug: Methylprednisolone (or other glucocorticoid); Drug: Prednisone

Interventions

Rituximab plus cyclophosphamide placebo (rituximab group) DRUG

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

Also known as: Rituxan

Rituximab

Cyclophosphamide plus rituximab placebo (control group) DRUG

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

Also known as: Cytoxan

Control Group

Azathioprine DRUG

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

Also known as: imuran

Control Group

Methylprednisolone (or other glucocorticoid) DRUG

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

Also known as: Medrol

Control Group; Rituximab

Prednisone DRUG

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.

Also known as: Deltasone, Liquid Pred, Meticorten, Orasone

Control Group; Rituximab

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• Genentech, Inc.: collaborator

Study Sites (8)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

Boston University

Boston, Massachusetts, 02118, United States

Location

Mayo Clinic Foundation

Rochester, Minnesota, 55905, United States

Location

Hospital for Special Surgery

New York, New York, 10128, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

The Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University Hospital Groningen

Groningen, 9713 GZ, Netherlands

Location

Related Publications (12)

• 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. No abstract available.

  PMID: 23902488 BACKGROUND

• 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. doi: 10.1056/NEJMoa0909905.

  PMID: 20647199 RESULT

• 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, Peikert T, Stegeman C, Ytterberg SR, Mueller M, Sejismundo LP, Mieras K, Stone JH; RAVE-ITN Research Group. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013 Aug 1;369(5):417-27. doi: 10.1056/NEJMoa1213277.

  PMID: 23902481 RESULT

• 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, Ikle D, Jepson B, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2013 Sep;65(9):2441-9. doi: 10.1002/art.38044.

  PMID: 23754238 RESULT

• Monach PA, Warner RL, Tomasson G, Specks U, Stone JH, Ding L, Fervenza FC, Fessler BJ, Hoffman GS, Ikle 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 reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. Ann Rheum Dis. 2013 Aug;72(8):1342-50. doi: 10.1136/annrheumdis-2012-201981. Epub 2012 Sep 12.

  PMID: 22975753 RESULT

• Nasrallah M, Pouliot Y, Hartmann B, Dunn P, Thomson E, Wiser J, Butte AJ. Reanalysis of the Rituximab in ANCA-Associated Vasculitis trial identifies granulocyte subsets as a novel early marker of successful treatment. Arthritis Res Ther. 2015 Sep 21;17(1):262. doi: 10.1186/s13075-015-0778-z.

  PMID: 26387933 RESULT

• Miloslavsky EM, Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Tchao NK, Ding L, Ikle D, Villareal M, Lim N, Brunetta P, Fervenza FC, Monach PA, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids. Arthritis Rheumatol. 2015 Jun;67(6):1629-36. doi: 10.1002/art.39104.

  PMID: 25776953 RESULT

• 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, Ikle D, Villarreal M, Jepson B, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Stone JH; Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network Research Group. Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 2014 Nov;66(11):3151-9. doi: 10.1002/art.38788.

  PMID: 25047592 RESULT

• Berti A, Hillion S, Hummel AM, Son YM, Chriti N, Peikert T, Carmona EM, Abdulahad WH, Heeringa P, Harris KM, St Clair EW, Brunetta P, Fervenza FC, Langford CA, Kallenberg CG, Merkel PA, Monach PA, Seo P, Spiera RF, Stone JH, Grandi G, Sun J, Pers JO, Specks U, Cornec D; RAVE-ITN Research Group. Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis. JCI Insight. 2021 Nov 22;6(22):e150999. doi: 10.1172/jci.insight.150999.

  PMID: 34618687 DERIVED

• Kronbichler A, Leierer J, Shin JI, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CGM, St Clair EW, Brunetta P, Fervenza FC, Geetha D, Keogh KA, Monach PA, Ytterberg SR, Mayer G, Specks U, Stone JH; RAVE-ITN Research Group. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2019 Nov;71(11):1888-1893. doi: 10.1002/art.41017. Epub 2019 Sep 25.

  PMID: 31216123 DERIVED

• Wallace ZS, Miloslavsky EM, Cascino M, Unizony SH, Lu N, Hoffman GS, Kallenberg CGM, Langford CA, Merkel PA, Monach PA, Seo P, Spiera R, St Clair EW, Specks U, Brunetta P, Choi HK, Stone JH. Effect of Disease Activity, Glucocorticoid Exposure, and Rituximab on Body Composition During Induction Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Care Res (Hoboken). 2017 Jul;69(7):1004-1010. doi: 10.1002/acr.23099.

  PMID: 27696762 DERIVED

• Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CM, St Clair EW, Ikle D, Tchao NK, Ding L, Brunetta P, Choi HK, Monach PA, Fervenza F, Stone JH, Specks U; RAVE-ITN Research Group. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016 Jun;75(6):1166-9. doi: 10.1136/annrheumdis-2015-208073. Epub 2015 Nov 30.

  PMID: 26621483 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network website
• Genentech website

MeSH Terms

Conditions

Vasculitis; Granulomatosis with Polyangiitis; Microscopic Polyangiitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

Interventions

Rituximab; Cyclophosphamide; Control Groups; Azathioprine; Methylprednisolone; Prednisone

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Systemic Vasculitis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols

Results Point of Contact

• Title: Associate Director, Clinical Research Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

(301) 594-7669

Study Officials

• John H. Stone, MD, MPH

  Johns Hopkins University

  STUDY CHAIR

• Ulrich Specks, MD

  Mayo Clinic

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2005
• First Posted: February 25, 2005
• Study Start: January 1, 2005
• Primary Completion: December 1, 2008
• Study Completion: January 1, 2010
• Last Updated: April 21, 2017
• Results First Posted: August 25, 2011

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will share

Locations

US (7); NL (1)