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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-000637-12 | EudraCT Number |
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| Name | Class |
|---|---|
| French Vasculitis Study Group | OTHER |
| URC-CIC Paris Descartes Necker Cochin | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Experimental | Experimental regimen: One year Glucocorticoid treatment and Rituximab IV 1 gram on Day 1 and 15 |
|
| Rituximab-Placebo | Placebo Comparator | Standard regimen: One-year Glucocorticoid treatment and Placebo-Rituximab IV on Day 1 and 15 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | 1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine |
|
| Measure | Description | Time Frame |
|---|---|---|
| Disease free survival rate | Failure free survival in patients with microscopic polyangiitis treated with rituximab and glucocorticoids compared to glucocorticoids alone.
| 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative dose of GC in each group | GC dose will be recorded at each visit | 18 months |
| Proportion of patients who achieve a complete remission defined by the absence of sign attributable to vasculitis and a BVAS=0 |
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Inclusion Criteria:
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:
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.
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| Name | Affiliation | Role |
|---|---|---|
| Luc Mouthon, MD PhD | Assistance Publique - Hôpitaux de Paris | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cochin Hospital | Paris | 75014 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25372085 | Background | 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. | |
| 23902481 |
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| ID | Term |
|---|---|
| D055953 | Microscopic Polyangiitis |
| D056648 | Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis |
| ID | Term |
|---|---|
| D059345 | Cerebral Small Vessel Diseases |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| placebo | Drug | Placebo-Rituximab 1 gram IV on Day 1 and 15 after premedication with 100 mg méthylprednisolone, 1 gramm paracetamol and 5 mg dexchlorpheniramine |
|
Absence of sign attributable to vasculitis and a BVAS=0 at M3
| 1 month |
| Compare proportion of patients who relapse and time to first relapse | 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 | 18 months |
| Among patients who relapse, proportion of major relapses | 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 | 18 months |
| Among patients who relapse, proportion of minor relapses | Minor relapse is defined by reappearance or worsening of disease with a BVAS≥1, not corresponding to a major relapse | 18 months |
| Mortality rate | Proportion will be compared between groups | 18 months |
| Quality of life:Short Form Health Survey Questionnaire (SF-36) | 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). | 18 months |
| Disability | 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). | 18 months |
| Disability | 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. | 18 months |
| Severity of sequels linked to vasculitis as | 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. | 18 months |
| Proportion of patients who still receive GC at the end of follow-up | Proportion will be compared between groups | 18 months |
| Number and severity of side effect. | 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. | 18 months |
| Background |
| 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. |
| 20647199 | 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. |
| 20647198 | Background | 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. |
| 24161361 | Background | 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. |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D056647 | Systemic Vasculitis |
| D014657 | Vasculitis |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |