Clinical trial NCT03920722: Efficacy and Safety of Rituximab in the Treatment of Good Prognosis Microscopic Polyangiitis
Official title: Efficacy and Safety of Rituximab in the Treatment of Good Prognosis Microscopic Polyangiitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Microscopic Polyangiitis (MPA)
Keywords: MPA
Rituximab
ANCA-associated vasculitis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: French Vasculitis Study Group
First posted: 2019-04-19
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

1. Patient (male or female) over 18 year old
2. Patient agree to participate in the study and signed written informed consent
3. Patient with MPA according to the CHCC established in 2012
4. Absence of any poor prognosis factor (modified five factor score (FFS) 1996 = 0)
5. 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.
6. Patient with anti-MPO antibody measured by enzyme - linked immunosorbent assay (ELISA).
7. 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:

1. Small-sized vessels vasculitis not associated to anti-MPO antibody or associated with anti-PR3 positivity.
2. Patients with either GPA or EGPA vasculitis according to ACR criteria
3. Patient with a modified FFS 1996 ≥ 1
4. Patient with alveolar hemorrhage requiring mechanical ventilation
5. Patient with previous glucocorticoids treatment \>1 month and \> 10mg/day either for vasculitis or for any other reason.
6. 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.
7. Patient with a previous diagnosis of cancer \< 5 years (except for in situ cervical cancer and skin carcinoma with R0 resection)
8. Patient with acute infections or chronic active infections (HIV, hepatitis B or C)
9. Breast feeding woman or woman refusing the use of a contraceptive method for the 18 months' duration of the study
10. Contraindication to treatment (glucocorticoids or rituximab)
11. Unable to receive written informed consent of patient. Patient unable to understand the protocol
12. Patient already in another therapeutic protocol
13. Patient without social security
14. Patient with severe cardiac failure defined as class IV in New York Heart Association classification or severe, uncontrolled cardiac disease.
15. Patients with hypersensitivity to a monoclonal antibody or biological agent.
16. Patients in a severely immunocompromised state.

Primary outcomes:
measure: Disease free survival rate
timeFrame: 18 months
Secondary outcomes:
measure: Cumulative dose of GC in each group
timeFrame: 18 months
measure: Proportion of patients who achieve a complete remission defined by the absence of sign attributable to vasculitis and a BVAS=0
timeFrame: 1 month
measure: Compare proportion of patients who relapse and time to first relapse
timeFrame: 18 months
measure: Among patients who relapse, proportion of major relapses
timeFrame: 18 months
measure: Among patients who relapse, proportion of minor relapses
timeFrame: 18 months
measure: Mortality rate
timeFrame: 18 months
measure: Quality of life:Short Form Health Survey Questionnaire (SF-36)
timeFrame: 18 months
measure: Disability
timeFrame: 18 months
measure: Disability
timeFrame: 18 months
measure: Severity of sequels linked to vasculitis as
timeFrame: 18 months
measure: Proportion of patients who still receive GC at the end of follow-up
timeFrame: 18 months
measure: Number and severity of side effect.
timeFrame: 18 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Cochin Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Luc Mouthon, MD PhD
role: STUDY_CHAIR
References:
citation: Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quemeneur T, Blanchard-Delaunay C, Godmer P, Puechal X, Carron PL, Hatron PY, Limal N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231.
citation: 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.
citation: 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.
citation: Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169.
citation: Samson M, Puechal X, Devilliers H, Ribi C, Cohen P, Bienvenu B, Ruivard M, Terrier B, Pagnoux C, Mouthon L, Guillevin L; French Vasculitis Study Group (FVSG). Long-term follow-up of a randomized trial on 118 patients with polyarteritis nodosa or microscopic polyangiitis without poor-prognosis factors. Autoimmun Rev. 2014 Feb;13(2):197-205. doi: 10.1016/j.autrev.2013.10.001. Epub 2013 Oct 23.