Rituximab Plus Corticosteroids in Non-infectious Active Mixed Cryoglobulinemia Vasculitis (ESBAM)

Multicenter Randomized Double-blind Study Comparing the Efficacy and Safety of Rituximab in Combination With Corticosteroids to Corticosteroids Plus Placebo in the Treatment of Non-infectious Active Mixed Cryoglobulinemia Vasculitis

Multicenter randomized double-blind study comparing the efficacy and safety of rituximab in combination with corticosteroids to corticosteroids plus placebo in the treatment of non-infectious active mixed cryoglobulinemia vasculitis.

Study Overview

• Status: Terminated
• Conditions: Systemic Vasculitis; Cryoglobulinemia
• Intervention / Treatment: Drug: Placebo; Drug: Prednisone; Drug: rituximab

Detailed Description

Cryoglobulinemia are responsible for systemic vasculitis, and the most frequently targeted organs are the skin, joints, kidneys and peripheral nervous system. Cryoglobulinemia vasculitis are associated with significant morbidity and mortality, and require therapeutic intervention. Management of non-infectious mixed cryoglobulinemia vasculitis is based on corticosteroids, plasma exchange, and/or immunosuppressants. These treatments are associated with frequent side effects. To date, no study has evaluated the efficacy and safety of these different therapeutic options, explaining the lack of recommendations.

Rituximab, a monoclonal antibody directed against CD20, has emerged as a novel therapeutic option in B-cell related disorders. Data from the French AutoImmunity and Rituximab (AIR) registry recently reported the positive effect of rituximab in non-infectious mixed cryoglobulinemia vasculitis. More recently, the multidisciplinary national French CryoVas survey also suggested a significant superiority of the combination corticosteroid plus rituximab compared to the corticosteroids alone in terms of complete clinical and immunological responses and corticosteroid sparing. However, no randomized controlled data addressing this issue has been published to date.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Pitié Salpétrière Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The patient must be at least 18 years of age or older, without any upper age limit
2. Patient informed and agreed to participate, and gave informed consent,
3. Patient with active cryoglobulinemia vasculitis define by positive cryoglobulinemia and a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement (no histological evidence needed if presence of purpura demonstrated),
4. Patient with primary Sjögren's syndrome, systemic lupus erythematosus, or another auto-immune disease, or B-cell non-Hodgkin lymphoma (with cryoglobulinemia as the only therapeutic indication), or essential mixed cryoglobulinemia,
5. Naive or relapsing patients, without modification (initiation or increase) of immunosuppressive therapy in the month prior the inclusion,
6. For women of child bearing age: negative pregnancy test during the inclusion, and effective contraception during the period of 12 months after the latest rituximab infusion or placebo,
7. Patients with severe vasculitis must be treated in the 15 days prior inclusion by 3 bolus of methylprednisolone (15 mg/kg/d) AND 3 to 7 plasma exchanges (exchange volume of 60 ml/kg/session).

Exclusion Criteria:

1. Patient with a medium and small size vessels vasculitis unrelated to cryoglobulinemia (granulomatous with polyangiitis (Wegener's disease), microscopic polyangiitis, eosinophilic granulomatous with polyangiitis (Churg-Strauss syndrome), polyarteritis nodose, IgA vasculitis, hypersensitivity vasculitis, infectious vasculitis, hypocomplementemic urticarial vasculitis),
2. Patient with a large size vessels vasculitis,
3. Patient with non active cryoglobulinemia vasculitis,
4. Patient with immunosuppressive therapy introduced or increased in the month prior to the inclusion,
5. Patients receiving corticosteroid therapy > 0.5 mg/kg/d for more than one month before the inclusion or > 1 mg/kg/d for more than two weeks before the inclusion,
6. Patient who had received rituximab therapy within the 12 months before the inclusion,
7. Pregnancy in progress or needed , breast feeding,
8. HIV-positive status,
9. Patient with active hepatitis B or C infection,
10. HBs Ag-positive and/or HBV DNA detectable in the blood*,
11. Patients with known hypersensitivity reaction to the active substance or any of the excipients, or to murine proteins,
12. Contraindication to rituximab,
13. Active infections at screening,
14. Patient in guardianship,
15. Patient already included in a biomedical research protocol,
16. No social security scheme (Beneficiaries or eligible),

17. History of cancer during the last 3 years before inclusion, including solid tumors, hematological malignancies (except lymphoproliferative disorder associated with the mixed cryoglobulinemia vasculitis), and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been treated or excized and cured)"

    • If the hepatitis B core antibody (anti-HBc) is positive, the benefit/risk will be evaluated by an hepatologist before inclusion, and patient, if enrolled, will be monitored until the end of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rituximab; Prednisone treatment plus rituximab administered by slow intravenous infusion at 375 mg/m2 at D1, D8, D15 and D22.	Drug: Prednisone; Drug: rituximab; Prednisone treatment plus rituximab administered by slow intravenous infusion at 375 mg/m2 at D1, D8, D15 and D22.
Placebo Comparator: placebo; Prednisone treatment plus placebo administered by slow intravenous infusion at day 1 (D1), D8, D15 and D22.	Drug: Placebo; Drug: Prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete clinical response of vasculitis symptoms (yes-no, i.e. success-failure) with corticosteroid withdrawal (prednisone at 0 mg/day) at week (W) 24, with at least one clinical response at W4	The complete clinical response is defined by the remission of all affected organs involved at baseline and the absence of clinical relapse.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Partial clinical response	Partial clinical response defined by an improvement of at least half of organ impairments present at baseline	Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolution of cryoglobulinemia (positive or negative)		Week 24
Evolution of C4 complement fraction (mg/L)		Week 24
Rate of early failures		Week 4
Occurrence of clinical relapse	Clinical relapse is defined by de novo appearance or reappearance of a manifestation attributable to cryoglobulinemia vasculitis during 48 weeks of follow-up,	up to Week 48
Cumulative dose of prednisone		Week 24
quality of life	evolution of quality of life will be assessed by the score SF36	Day 1
quality of life	evolution of quality of life will be assessed by the score SF36	Week 4
quality of life	evolution of quality of life will be assessed by the score SF36	Week 8
quality of life	evolution of quality of life will be assessed by the score SF36	Week 16
quality of life	evolution of quality of life will be assessed by the score SF36	Week 24
quality of life	evolution of quality of life will be assessed by the score SF36	Week 36
quality of life	evolution of quality of life will be assessed by the score SF36	Week 48
quality of life at relapse	quality of life at relapse will be assessed by the score SF36	up to Week 48
Infusion related reactions	hypersensitivity reaction rate such as fall in blood pressure, bronchospasm, … due to rituximab or placebo infusions (included also reaction occurring after the end of infusion),	up to Week 4
Rate of infections (severe or not) and other complications related to corticosteroids		up to Week 48

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Patrice CACOUB, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2015
• Primary Completion (Actual): May 31, 2018
• Study Completion (Actual): May 31, 2018

Study Registration Dates

• First Submitted: July 20, 2015
• First Submitted That Met QC Criteria: September 21, 2015
• First Posted (Estimate): September 22, 2015

Study Record Updates

• Last Update Posted (Actual): March 18, 2019
• Last Update Submitted That Met QC Criteria: March 14, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Vasculitis; Systemic Vasculitis; Cryoglobulinemia; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Rituximab; Prednisone
• Other Study ID Numbers: P120122; 2013-000844-24 (EudraCT Number)