RITUXGOPRO: Efficacy and Safety of Rituximab in the Treatment of Good Prognosis Microscopic Polyangiitis

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Recruiting

CT.gov ID

NCT03920722

Collaborator

French Vasculitis Study Group (Other)

106

Enrollment

Location

Arms

41.2

Anticipated Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to determine wether a rituximab-based treatment compared to standard therapy (glucocorticoid alone) in patients with microscopic polyangiitis without any bad prognosis marker increases the remission and reduces the relapse free survival rate.

Condition or Disease	Intervention/Treatment	Phase
Microscopic Polyangiitis (MPA)	Drug: Rituximab Drug: placebo	Phase 3

Detailed Description

Microscopic polyangiitis (MPA), is a small-sized vessel necrotizing vasculitis associated with anti-neutrophils cytoplasmic antibody (ANCA). Treatment of ANCA associated vasculitis (AAV) was previously based on glucocorticoids (GC) and cyclophosphamide. It has been demonstrated in two prospective randomized trials that rituximab is as effective as cyclophosphamide in the induction treatment of GPA and severe MPA. In addition, it was shown in GPA and MPA that rituximab is superior to azathioprine as maintenance therapy.

Patients with MPA without poor prognosis factor (Five factor score (FFS)=0) have not been included in the previous studies and GC alone is considered as the reference treatment in these patients. However, as much as 50% of these patients experience relapses after a 24 months follow-up and only 40% of patients have a long lasting remission.

In the group of patients with MPA without any poor prognosis factor (FFS=0), an additional treatment with rituximab might decrease the relapse rate from 40% to 15% after an 18 months' follow-up. The efficacy and safety of this proposal must be tested.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

106 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Efficacy and Safety of Rituximab in the Treatment of Good Prognosis Microscopic Polyangiitis

Actual Study Start Date :

Oct 24, 2020

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Apr 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab Experimental regimen: One year Glucocorticoid treatment and Rituximab IV 1 gram on Day 1 and 15	Drug: Rituximab 1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine
Placebo Comparator: Rituximab-Placebo Standard regimen: One-year Glucocorticoid treatment and Placebo-Rituximab IV on Day 1 and 15	Drug: placebo Placebo-Rituximab 1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine

Arm

Intervention/Treatment

Experimental: Rituximab

Experimental regimen: One year Glucocorticoid treatment and Rituximab IV 1 gram on Day 1 and 15

Drug: Rituximab

1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine

Placebo Comparator: Rituximab-Placebo

Standard regimen: One-year Glucocorticoid treatment and Placebo-Rituximab IV on Day 1 and 15

Drug: placebo

Placebo-Rituximab 1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine

Outcome Measures

Primary Outcome Measures

Disease free survival rate [18 months]
Failure free survival in patients with microscopic polyangiitis treated with rituximab and glucocorticoids compared to glucocorticoids alone. Primary failure: Vasculitis requiring a modification of immunosuppressive treatment or prednisone tapering protocol before M3 Remission is defined by the absence of sign attributable to vasculitis and a Birmingham Vasculitis Activity Score (BVAS)=0 at M3 Relapse is defined after visit M3 by a BVAS>0 or the impossibility to decrease glucocorticoids according to the predefined protocol. Therefore, patients who experience a primary failure or fail to enter remission or relapse will be considered as treatment failure. Death will also be considered as a treatment failure

Secondary Outcome Measures

Cumulative dose of GC in each group [18 months]
GC dose will be recorded at each visit
Proportion of patients who achieve a complete remission defined by the absence of sign attributable to vasculitis and a BVAS=0 [1 month]
Absence of sign attributable to vasculitis and a BVAS=0 at M3
Compare proportion of patients who relapse and time to first relapse [18 months]
Relapse is defined after visit M3 by the reoccurrence of signs or symptoms attributable to vasculitis and a BVAS≥1 or the impossibility to decrease GC therapy according to the predefined protocol
Among patients who relapse, proportion of major relapses [18 months]
Major relapse is defined by reappearance or worsening of disease with a BVAS≥1 and involvement of at least one major organ, a life-threatening manifestation, or both
Among patients who relapse, proportion of minor relapses [18 months]
Minor relapse is defined by reappearance or worsening of disease with a BVAS≥1, not corresponding to a major relapse
Mortality rate [18 months]
Proportion will be compared between groups
Quality of life:Short Form Health Survey Questionnaire (SF-36) [18 months]
Assessed by mean variation of the SF-36 The 36-Item Short Form Health Survey questionnaire (SF-36) questionnaire includes 36 items related to eight health component (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health.) A scale has been established for each component and results vary from 0 (bad health perception) to 100 (good health perception).
Disability [18 months]
Assessed by the mean variation of the Health Assessment Questionnaire (HAQ) Health Assessment Questionnaire (HAQ) is a questionnaire that evaluates the disability of the patient. Results vary from 0 (no assistance is needed) to 3 (patient usually needs both a special device and help from another person).
Disability [18 months]
Assessed by the mean variation of the Euroqol 5D (EQ-5D). The EuroQol-5 dimension (EQ-5D-3L) is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D is made up of five dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression), each of which can be rated at one of three levels (no problem, some problems, extreme/severe problems). The EuroQol questionnaire also contains a visual analogue scale (EQ-VAS), where patients are asked to rate their current health state on a 0 (worst imaginable health state) to 100 (best imaginable health state) scale.
Severity of sequels linked to vasculitis as [18 months]
Assessed by comparison of the VDI score. The Vascular Damage index score documents any organ damage that has occurred in patients since the onset of vasculitis. The score includes 64 items that are categorized into 11 groups (by organ system) and result is the summ of each damaged items.
Proportion of patients who still receive GC at the end of follow-up [18 months]
Proportion will be compared between groups
Number and severity of side effect. [18 months]
Record of adverse events and serious adverse events related to vasculitis or treatment in each group. Classification is made according to the CTCAE toxicity grading system.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient (male or female) over 18 year old
Patient agree to participate in the study and signed written informed consent
Patient with MPA according to the CHCC established in 2012
Absence of any poor prognosis factor (modified five factor score (FFS) 1996 = 0)
Patient with recent onset or relapse of the disease (<1 month) defined by BVAS > 0, who did not received any other treatment than glucocorticoids during last month. For patients with a BVAS<3, activity of vasculitis (either relapse or new onset) has to be confirmed by the coordinating investigator. One to 3 initial glucocorticoids pulse(s) are allowed.
Patient with anti-MPO antibody measured by enzyme - linked immunosorbent assay (ELISA).
Negative pregnancy test (serum β-hCG) for women of child-bearing potential and a willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study and 12 months after stopping therapy

Exclusion Criteria:

Small-sized vessels vasculitis not associated to anti-MPO antibody or associated with anti-PR3 positivity.
Patients with either GPA or EGPA vasculitis according to ACR criteria
Patient with a modified FFS 1996 ≥ 1
Patient with alveolar hemorrhage requiring mechanical ventilation
Patient with previous glucocorticoids treatment >1 month and > 10mg/day either for vasculitis or for any other reason.
Patient already receiving immunosuppressant or biological agent.

Prior treatment with any of the following:

azathioprine, methotrexate, mycophenolate mophetil, mycophenolic acid within 4 weeks before inclusion
alkylant agent such as cyclophosphamide within 6 months before inclusion
anti-TNF inhibitors : infliximab within 8 weeks, adalimumab and etanercept within 2 weeks before inclusion
anti-CD20 therapy within one year before inclusion.

Patient with a previous diagnosis of cancer < 5 years (except for in situ cervical cancer and skin carcinoma with R0 resection)
Patient with acute infections or chronic active infections (HIV, hepatitis B or C)
Breast feeding woman or woman refusing the use of a contraceptive method for the 18 months' duration of the study
Contraindication to treatment (glucocorticoids or rituximab)
Unable to receive written informed consent of patient. Patient unable to understand the protocol
Patient already in another therapeutic protocol
Patient without social security
Patient with severe cardiac failure defined as class IV in New York Heart Association classification or severe, uncontrolled cardiac disease.
Patients with hypersensitivity to a monoclonal antibody or biological agent.
Patients in a severely immunocompromised state.