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Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing (MAINTANCAVAS)

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ClinicalTrials.gov Identifier: NCT02749292
Recruitment Status : Recruiting
First Posted : April 22, 2016
Last Update Posted : August 21, 2018
Sponsor:
Information provided by (Responsible Party):
John L Niles, Massachusetts General Hospital

Brief Summary:
The purpose of this study is to determine the best management strategy to maintain remission in patients with ANCA vasculitis who have been treated with rituximab induced B cell depletion for at least two years. This study will compare intermittent B Cell depletion upon B cell return or intermittent B cell depletion upon serologic relapse.

Condition or disease Intervention/treatment Phase
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Drug: Rituximab Phase 4

Detailed Description:

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease characterized by small vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO). Immunosuppressive therapy can result in remission; however, many patients relapse, which results in additional injury.

Rituximab, a humanized murine monoclonal antibody directed against CD20 located on the surface of B-lymphocytes (B cells), is effective in depleting B cells. The RAVE and RITUXVAS trials have shown efficacy of rituximab with steroids for induction of remission in ANCA vasculitis, similar to cyclophosphamide and steroids. Rituximab is now FDA-approved for induction of remission therapy in ANCA vasculitis. The utility of anti-B-cell therapy for early induction of remission in ANCA vasculitis is not surprising given that ANCA are pathogenic in vitro and in vivo. It is clear that remission in many patients is not sustained with a single induction course of rituximab, and relapses often occur after B cell re-population suggesting that scheduled, serial dosing of rituximab could result in sustained remissions.

Despite yielding promising outcomes, rituximab is also associated with a number of adverse events including infectious complications and late onset of neutropenia5, 15. Furthermore, the complications of continuous B cell depletion for extended durations are unknown. One of the major goals in the field is to utilize prolonged B cell depletion only in the subpopulation of patients where the risk of disease relapse outweighs the risk of treatment-related adverse events.

A rise in ANCA titers and reconstitution of B cells are promising biomarkers of impending disease relapse following treatment with rituximab4-6

A prospective and longitudinal clinical trial is needed to determine the ideal treatment strategy for long-term maintenance of remission. We propose to compare intermittent rituximab dosing based on B cell return and a serologic ANCA flare

The study design is an open-label, single center, randomized and two-arm controlled trial to evaluate the optimal maintenance of remission strategy that provides the best relapse-free survival in patients with ANCA vasculitis as determined by relapse-free remission at 18, 24 and 36 months from enrollment. The investigators are looking to enroll and randomize 200 subjects with ANCA vasculitis on rituximab-induced continuous B cell depletion for a minimum of two years to one of two arms as follows:

  1. Intermittent B cell depletion with rituximab re-dosing upon B cell return: Subjects will not receive their regularly-scheduled every-six-month dose of rituximab and will instead receive rituximab 1000 mg IV x 2 doses (spaced 2-3 weeks apart) once peripheral B cells return ( ≥ 10 B cells/mm3). This cycle will then re-start. Subjects will be seen in clinic every three months.
  2. Hold continuous dosing with rituximab with re-dosing upon a significant ANCA titer increase: For MPO, a significant increase will be defined as a 5-fold rise in ANCA titer and a level greater than 4 times the cutoff value for the assay. For PR3, a significant rise will be defined as a 4-fold rise in ANCA titer to a level at least twofold above the cutoff for the assay. Subjects will not receive regularly scheduled every six-month doses of rituximab and will instead be monitored every three months. Subjects who sustain a significant increase in ANCA titer will receive rituximab 1000mg IV x 2 doses, ~2-3 weeks apart. If the ANCA titer remains two-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO) , subjects will continue to receive rituximab 1000mg IV every 6 months for a maximum of 2 doses, at which time a new baseline ANCA titer will be established and the cycle will re-start.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Maintenance of ANCA Vasculitis Remission by Intermittent Rituximab Dosing Based on B-cell Reconstitution vs a Serologic ANCA Flare
Study Start Date : June 2016
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vasculitis
Drug Information available for: Rituximab

Arm Intervention/treatment
Active Comparator: B cell reconstitution
Subjects will no longer receive regularly-scheduled every six-month doses of rituximab (1000mg IV) and will instead be monitored every three months for B cell return. Once peripheral B cells rise to ≥ 10cells/mm3 they will receive rituximab 1000 mg IV x 2 (doses spaced approx. 2-3 weeks apart). Subsequent dosing will be again based on B cell return (≥ 10 B cells/mm3), with patients seen in clinic and B cells monitored every 3 months.
Drug: Rituximab
re-dosing dependent on interventional arm parameter.
Other Name: Rituxan

Active Comparator: Serologic ANCA flare
Subjects will not receive regularly-scheduled every six-month doses of rituximab (1000mg IV) and will instead be monitored every three months in clinic. Re-dosing will occur once the subject's ANCA titer has risen above the predetermined treatment value (MPO treatment value defined as a 5-fold rise from baseline and a level greater than 4 times the cutoff value for the assay; PR3 treatment value defined as a 4-fold rise from baseline and a level greater than 2-fold above the cutoff for the assay). Subjects who meet this criteria will then be re-dosed with rituximab 1000 mg IV x2 (spaced 2-3 weeks apart). If the ANCA titer remains 2-fold above baseline and above a specified threshold (the cutoff value of the assay for PR3 and 4 times the cutoff value for MPO), subjects will then receive rituximab 1000mg IV every 6 months x 2 doses and a new ANCA titer baseline will be established. The cycle will then re-start.
Drug: Rituximab
re-dosing dependent on interventional arm parameter.
Other Name: Rituxan




Primary Outcome Measures :
  1. Number of disease relapses as defined by a Birmingham Vasculitis Activity Score for Wegner's Granulomatosis (BVAS/WG) ≥ 2 [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Number of serious adverse events [ Time Frame: 3 years ]
  2. Composite of disease relapse (defined a BVAS/WG ≥ 2) and serious adverse events [ Time Frame: 3 years ]
  3. Hypogammaglobulinemia defined as an IgG < 400 mg/dL [ Time Frame: 3 years ]
  4. Patient Survival [ Time Frame: 3 years ]
  5. Health-related quality of life as assessed by the Short Form Health Survey (SF-36) score [ Time Frame: 3 years ]
  6. Rituximab utilization measured in grams/patient [ Time Frame: 3 years ]
  7. Organ damage as assessed by the Vasculitis Damage Index (VDI) [ Time Frame: 3 years ]
  8. Number of major relapses defined as a BVAS/WG ≥ 3 [ Time Frame: 3 years ]
  9. Number of infections defined as receiving oral or IV antibiotics [ Time Frame: 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 82 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All patients must be able and willing to give written informed consent and comply with the requirements of the study protocol.
  2. Diagnosis: ANCA vasculitis as defined by a positive MPO- and/or PR3-ANCA test together with clinical features characteristic of ANCA-positive diseases as detailed in the 2012 Chapel Hill Consensus Conference Definitions(18).
  3. eGFR ≥ 30 cc/min/1.73m2
  4. Age: 18-82 years old
  5. Treated with rituximab-induced continuous B cell depletion and in remission (defined by a modified BVAS-WG=0 AND a prednisone dose of ≤ 7.5 mg) for at least 24 months.
  6. CD20 (B cells) undetectable at time of enrollment/randomization
  7. Urine Hcg negative for women of child bearing potential and not planning to become pregnant for at least 12 months from enrollment and at least 12 months after any study related rituximab dose
  8. Judged to be otherwise healthy by the Investigator, based on medical history and physical examination (no known active disease process for which life expectancy is less than 36 months)

Exclusion Criteria:

  1. Secondary Disease: disease suspected to be induced by levamisole-adulterated cocaine
  2. All transplanted patients
  3. Treatment: additional immunosuppressive agents other than rituximab and/or total daily prednisone dose ≥ 7.5 milligrams
  4. Hypogammaglobulinemia: IgG level < 250 mg/dL
  5. Terminal cancer or other primary illness with life expectancy of less than 36 months
  6. Active anti-GBM disease and other known autoimmune disease for which the need for additional immunosuppression is likely
  7. Pregnancy or breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02749292


Contacts
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Contact: John L Niles, MD 617-726-4132 jlniles@partners.org
Contact: Karen Laliberte, RN, MSN 617-726-4132 klaliberte@partners.org

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Karen Laliberte, MSN    617-726-4132    klaliberte@partners.org   
Contact: Andrew Murphy, MBA    617-726-4132    apmurphy@partners.org   
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
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Principal Investigator: John L Niles, MD Massachusetts General Hospital

Publications:

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Responsible Party: John L Niles, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02749292     History of Changes
Other Study ID Numbers: 2015P002541
First Posted: April 22, 2016    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by John L Niles, Massachusetts General Hospital:
rituximab
maintenance
remission

Additional relevant MeSH terms:
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Vasculitis
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Systemic Vasculitis
Vascular Diseases
Cardiovascular Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents