Comparison Between a Long Term and a Conventional Maintenance Treatment With Rituximab (MAINRITSAN3)

• ClinicalTrials.gov Identifier: NCT02433522
• Recruitment Status: Completed
• First Posted: May 5, 2015
• Last Update Posted: April 19, 2021
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: Roche Pharma AG
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: March 23, 2015
• First Posted Date: May 5, 2015
• Last Update Posted Date: April 19, 2021
• Actual Study Start Date: March 31, 2015
• Actual Primary Completion Date: August 16, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 29, 2015)

Vasculitis score 2003 (BVAS 2003 ) [ Time Frame: 28 months ]

Relapse free survival rates (BVAS > 0)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 29, 2015)

• Number of adverse events, [ Time Frame: 28 months ]
  adverse events including infectious effects and their severity in each arm
• number of patients experiencing at least one adverse event in both arms [ Time Frame: 28 months ]
• correlation of ANCA level with the clinical events [ Time Frame: 28 months ]
• ANCA level during follow-up [ Time Frame: 28 months ]
• correlation B-Lymphocytes CD-19 level with the clinical events [ Time Frame: 28 months ]
• B-Lymphocytes CD-19 level during follow-up [ Time Frame: 28 months ]
• number of B memory cells during follow-up in both arms [ Time Frame: 28 months ]
• correlation number of B memory cells with the clinical events [ Time Frame: 28 months ]
• Number of patients with ANCA in each arm [ Time Frame: 28 months ]
• Time frame to death in both arms [ Time Frame: 28 months ]
• time frame of first minor relapse [ Time Frame: 28 months ]
• time frame of first major relapse [ Time Frame: 28 months ]
  "the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both"
• Cumulated dose of corticosteroid treatment [ Time Frame: 28 months ]
• Number and severity of damages [ Time Frame: 28 months ]
• number of of gammaglobulins [ Time Frame: 28 months ]
• Quality of life : SF36 (The Short Form (36) Health Survey) [ Time Frame: 28 months ]
• functional capacities : HAQ (Health Assessment Questionnaire ) [ Time Frame: 28 months ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Comparison Between a Long Term and a Conventional Maintenance Treatment With Rituximab
• Official Title: Extended Follow Up of the Mainritsan 2 Study. Comparison Between a Long Term and a Conventional Maintenance Treatment With Rituximab: a Placebo- Controlled Randomized Trial

Brief Summary

MAINRITSAN study compared Rituximab and azathioprine as maintenance therapy for ANCA-associated vasculitides. In this study, Rituximab (5 infusions at D1, D15, M6, M12, M18) was superior to azathioprine (2 mg/kg/day) to prevent relapses of AAV 28 months after the inclusion (Guillevin et al. NEJM 2014). Nevertheless, in the follow-up study of MAINRITSAN, up to 30% of patients experienced a relapse 38 months after the last rituximab infusion (unpublished data). Right now, no randomized controlled study has been carried in order to evaluate the best duration of the maintenance treatment with rituximab.

The investigators objective is to evaluate the efficacy of a long term rituximab treatment to prevent relapses of ANCA-associated vasculitis in patients in remission after a first phase of rituximab maintenance treatment.

The investigators will conduct a randomized placebo-controlled trial of a long term rituximab maintenance treatment (46 months) against a conventional maintenance treatment (18 months).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: ANCA-associated Vasculitides

Intervention

• Drug: rituximab
  500 mg rituximab infusion at the randomization visit and every 6 months for 18 months. Each infusion will be preceded by an infusion of 1000 mg paracetamol, 100 mg methylprednisolone and 5 mg dexchlorpheniramine.
• Drug: Placebo

Study Arms

• Experimental: Rituximab
  500 mg rituximab infusion at the randomization visit and every 6 months for 18 months
  Intervention: Drug: rituximab
• Placebo Comparator: Placebo
  Placebo infusion at the randomization visit and every 6 months for 18 months
  Intervention: Drug: Placebo

Publications *

• Pagnoux C, Guillevin L; French Vasculitis Study Group; MAINRITSAN investigators. Rituximab or azathioprine maintenance in ANCA-associated vasculitis. N Engl J Med. 2015 Jan 22;372(4):386-7. doi: 10.1056/NEJMc1414728. No abstract available.
• Charles P, Perrodeau E, Samson M, Bonnotte B, Neel A, Agard C, Huart A, Karras A, Lifermann F, Godmer P, Cohen P, Hanrotel-Saliou C, Martin-Silva N, Pugnet G, Maurier F, Sibilia J, Carron PL, Gobert P, Meaux-Ruault N, Le Gallou T, Vinzio S, Viallard JF, Hachulla E, Vinter C, Puechal X, Terrier B, Ravaud P, Mouthon L, Guillevin L; French Vasculitis Study Group. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med. 2020 Aug 4;173(3):179-187. doi: 10.7326/M19-3827. Epub 2020 Jun 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 14, 2016): 97
• Original Estimated Enrollment (submitted: April 29, 2015): 118
• Actual Study Completion Date: August 16, 2018
• Actual Primary Completion Date: August 16, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

First, patients must have been included in MAINRITSAN 2 and in addition to meeting the criteria for inclusion and non-inclusion.

MAINRITSAN 2 inclusion criteria:

• Granulomatosis with Polyangiitis Or microscopic polyangiitis complying Or kidney-limited disease With or without detectable ANCA (anti-neutrophil cytoplasmic antibodies) at the time of diagnosis or relapse, and at remission.
• Who have achieved remission using a treatment combining corticosteroids and an immunosuppressive agent, including corticosteroids, cyclophosphamide IV or oral (the use of another immunosuppressant is allowed, according to the current French guidelines, as well as plasma exchanges and/or IV immunoglobulins, or rituximab).
• Interval of 1 month between the end of the immunosuppressant treatment and the randomization time if cyclophosphamide or methotrexate were used, interval between 4 and 6 months if rituximab was used
• Age > 18 years without age limit higher when the diagnosis is confirmed.
• Informed and having signed the consent form to take part in the study.

and Patients must meet all of the following criteria:

• In complete remission (BVAS 0) at 28 months of MAINRITSAN2 study.
• Informed patient who accepted to participate in MAINRITSAN 2 and who signed the informed consent to this extension.
• Randomized on the day of the evaluation of the primary endpoint of MAINRITSAN 2 during the visit M28 (last visit of the protocol).

Exclusion Criteria:

• Eosinophilic granulomatosis with polyangiitis (EGPA)
• History of severe allergic manifestations or anaphylactic manifestations following humanized or murine monoclonal antibodies infusions
• Pregnant or breast feeding women. Contraception is required for women who could be pregnant during treatment follow up and during the year following the last infusion.
• Infection by HIV (positive serology), HCV (positive serology), or HBV (HBsAg positive or anti-HBc antibody positive with anti-HBs antibody negative)
• Uncontrolled infection at time of inclusion in the extended follow-up study.
• Other severe bacterial, viral , mycobacterial or fungal infection(s), occurring within the last 3 months before of randomization. A severe infection is defined by the hospitalization, a life or organ threatening.
• Severe chronic obstructive bronchopathy (FEV < 50% or dyspnea stage III).
• Cardiac failure, stage IV according to the NYHA classification.
• Recent history of coronary artery disease (<1 month).
• Ongoing malignancy or hematologic disease within 5 years before inclusion.
• Patient with severe immunodepression characterized by clinical manifestations.
• Participation to another concomitant therapeutic study (except observational studies or studies without therapeutic intervention).
• Psychiatric disease that may interfere with the study.
• Non affiliation to a health insurance.
• Uncontrolled severe cardiac disease.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02433522
• Other Study ID Numbers: P110146 extended; 2012-001963-66 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Assistance Publique - Hôpitaux de Paris
• Original Responsible Party: Same as current
• Current Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Original Study Sponsor: Same as current
• Collaborators: Roche Pharma AG

Investigators

• Study Chair: Loic GUILLEVIN, MD-PhD; Assistance Publique - Hôpitaux de Paris

• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: April 2021