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

• ClinicalTrials.gov Identifier: NCT03920722
• Recruitment Status: Not yet recruiting
• First Posted: April 19, 2019
• Last Update Posted: April 19, 2019
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborator: French Vasculitis Study Group
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

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 (Clinical Trial)
• Estimated 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
• Estimated Study Start Date: September 2019
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 2023

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

Outcome Measures

Primary Outcome Measures :

1. Disease free survival rate [ Time Frame: 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.

Secondary Outcome Measures :

1. Cumulative dose of GC in each group [ Time Frame: 18 months ]
   GC dose will be recorded at each visit
2. Proportion of patients who achieve a complete remission defined by the absence of sign attributable to vasculitis and a BVAS=0 [ Time Frame: 1 month ]
   Absence of sign attributable to vasculitis and a BVAS=0 at M3
3. Compare proportion of patients who relapse and time to first relapse [ Time Frame: 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
4. Among patients who relapse, proportion of major relapses [ Time Frame: 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
5. Among patients who relapse, proportion of minor relapses [ Time Frame: 18 months ]
   Minor relapse is defined by reappearance or worsening of disease with a BVAS≥1, not corresponding to a major relapse
6. Mortality rate [ Time Frame: 18 months ]
   Proportion will be compared between groups
7. Quality of life:Short Form Health Survey Questionnaire (SF-36) [ Time Frame: 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).
8. Disability [ Time Frame: 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).
9. Disability [ Time Frame: 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.
10. Severity of sequels linked to vasculitis as [ Time Frame: 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.
11. Proportion of patients who still receive GC at the end of follow-up [ Time Frame: 18 months ]
    Proportion will be compared between groups
12. Number and severity of side effect. [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 ≥ 3, who did not received any other treatment than glucocorticoids during last month. 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.

Contacts and Locations

Contacts

Contact: Alexis REGENT, MD; +33 1 58 41 14 55; alexis.regent@aphp.fr

Contact: Alexandra BRUNEAU; +33 1 58 41 12 13; alexandra.bruneau@aphp.fr

Locations

France

Cochin Hospital

Paris, France, 75014

Contact: Alexis REGENT, MD +33 1 58 41 14 55 alexis.regent@aphp.fr

Contact: Luc Mouthon, MD, PhD +33 1 58 41 20 31 luc.mouthon@aphp.fr

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

French Vasculitis Study Group

Investigators

• Study Chair: Luc Mouthon, MD PhD; Assistance Publique - Hôpitaux de Paris

More Information

Publications:

Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quémeneur T, Blanchard-Delaunay C, Godmer P, Puéchal 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.

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.

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.

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.

Samson M, Puéchal 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.

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03920722
• Other Study ID Numbers: P170909J; 2018-000637-12 ( EudraCT Number )
• First Posted: April 19, 2019
• Last Update Posted: April 19, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

MPA; Rituximab; ANCA-associated vasculitis

Additional relevant MeSH terms:

Microscopic Polyangiitis; Systemic Vasculitis; Vasculitis; Vascular Diseases; Cardiovascular Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Immune System Diseases; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents