Evaluation of Glucocorticoids Plus Rituximab Compared to Glucocorticoids Plus Placebo for the Treatment of Patients With Newly-Diagnosed or Relapsing IgA Vasculitis

Study Overview
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Brief Summary
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Systemic vasculitis are inflammatory diseases of the blood vessels, responsible for systemic manifestations. Among the systemic vasculitis affecting small blood vessels, IgA vasculitis (IgAV) is one of the most common forms and mainly affects the skin, joints, kidneys and gastrointestinal tract. Kidney and gastrointestinal damage can be serious, causing complications and life-threatening sequelae, especially in adults. The treatment of adult-onset IgAV is still a matter of debate. Glucocorticoids have been the standard of care for inducing remission for years in severe forms of IgAV. However, not all patients achieve remission and may experience disease flares associated with increased morbidity and mortality. In addition, the cumulative side effects of glucocorticoids are also major causes of long-term adverse events and death.Rituximab (RTX), an anti-CD20 monoclonal antibody, has been shown to be spectacularly effective in inducing remission in d 'other small vascular vessels, in particular ANCA-associated vasculitis and cryoglobulinemic vasculitis, with an acceptable safety profile. Recently, a multicenter observational study suggested that RTX was an effective and safe therapeutic option for treating relapsed and / or refractory adult IgAV. Overall, RTX may be an effective and safe therapeutic approach in adult IgAVs, justifying the need for a prospective randomized controlled trial evaluating Rituximab as an induction of remission for adult IgAV.

Official Title
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Evaluation of Glucocorticoids Plus Rituximab Compared to Glucocorticoids Plus Placebo for the Treatment of Patients With Newly-Diagnosed or Relapsing IgA Vasculitis: A Prospective, Randomized, Controlled, Double-blind Study

Conditions
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IgA Vasculitis

Intervention / Treatment
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* Drug: Rituximab Injection
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-proven diagnosis of IgAV according to Chapel Hill Consensus Conference definitions Patient aged of 18 years or older Patients with newly-diagnosed disease or relapsing disease at the time of screening, with an active disease defined by active manifestations attributable to IgAV Patients with severe involvement of at least one organ Patients within the first 21 days following initiation/increase of glucocorticoids at a dose < 1 mg/kg/day Has signed an informed consent form prior to any study related procedures Affiliated to a national health insurance Exclusion Criteria: Patients with ANCA-associated vasculitis, or other vasculitis, defined by the ACR criteria and/or the Chapel Hill Consensus Conference, Patients with IgAV in remission of the disease, Patients with severe cardiac failure defined as class IV in New York Heart Association, Patients with severe, uncontrolled cardiac disease, Patients with acute infections or chronic active infections (including HIV, HBV or HCV), Patients with active cancer or recent malignancy (<5 years), except basocellular carcinoma and prostatic cancer of low activity controlled by hormonal treatment, Pregnant women and breastfeeding. Patients with childbearing potential must use reliable contraceptive methods throughout the study and at least for 12 months after the last study drug administration, Patients with IgAV who have already been treated with rituximab within the previous 12 months, Patients treated with immunosuppressive therapy within the last 3 months, Patients with hypersensitivity to human or chimeric monoclonal antibodies, Patients with contraindication to use rituximab, Patients treated with any concomitant drugs contraindicated for use with the rituximab according to its SmPC, Patients with contraindication to use routine care treatments (Glucocorticoids, Angiotensin-converting-enzyme (ACEis) or angiotensin receptor blockers (ARBs), dexchlorphéniramine), Patients in a severely immunocompromised state, Patients with other uncontrolled diseases, including drug or alcohol abuse, severe psychiatric disorders, that could interfere with his/her compliance to protocol requirements, Patients currently participating in another clinical study or 3 months prior to randomization, Patients suspected not to be observant to the proposed treatments, Patients unable to give written informed consent prior to participation in the study Being deprived of liberty or under guardianship.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Design of trial : Controlled (the comparator is a Placebo) Randomised Double blind Parallel groupe With a double layering
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental group<br>Experimental therapeutic strategy based on the use of rituximab in combination with glucocorticoids | Drug: Rituximab Injection<br>* anti-CD20 monoclonal antibody leading to B-cell depletion, in relapsing and/or refractory IgAV patients<br>* Other names: Truxima;|
| Placebo Comparator: control group<br>Control therapeutic strategy based on glucocorticoids plus placebo | Drug: placebo<br>* placebo experimental treatment<br>* Other names: NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rituximab efficacy | The proportion of patients alive who achieved remission with a prednisone dose of 0 mg/day at both days 180 and 360 | 360 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rituximab efficacy delay | Proportion of patients in remission at different research times | 360 days | 
| Rituximab efficacy delay | Proportion of patients with BVAS=0 (or BVAS of ≤5 if all scores were due to persistent hematuria or proteinuria) and a prednisone dose ≤5 mg/day at days 180 and 360 | 360 days | 
| IgAV relapses | Number of major and minor relapse at 12 months | 180 days | 
| IgAV relapses | Cumulative incidence of relapse at 12 months | 180 days | 
| IgAV relapses | Time to first IgAV relapse | 180 days | 
| Number of participants with adverse events for the safety analyse | Adverse events, expressed as adverse events according to the CTCAE toxicity grading system per patient-year at days 180 and 360 for the following adverse events combined: death (all causes), grade 2 or higher leukopenia or thrombocytopenia, grade 3 or higher infections, malignancies, venous thromboembolic events, hospitalization resulting either from the disease or from a complication due to the study treatment, infusion reactions (within 24 hours of infusion) that result in the cessation of further infusions, death | 360 days | 
| The glucocorticoids dose | Prednisone dosage at days 180 and 360 in the two treatment groups | 360 days | 
| The glucocorticoids dose | Area under the curve for prednisone dose at days 180 and 360 in the two treatment groups | 360 days | 
| Number of patients with a complete or partial renal remission & renal outcome remission | Proportion of patients in complete renal and partial renal remission at days 180 and 360; - Renal parameters at days 180 and 360 compared with baseline | 360 days | 
| Number of patients with a complete or partial renal remission & renal outcome remission | Renal parameters at days 180 and 360 compared with baseline | 360 days | 
| The sequelae assessed by the Vasculitis Damage Index | The Vasculitis Damage Index at days 180 and 360 in the two treatment groups | 360 days | 
| Patient survival and quality of life | Quality of life as measured by the HAQ and SF-36 questionnaires at days 180 and 360 | 360 days | 
| Patient survival and quality of life | The patient-reported outcomes (PRO) including patient-reported disease activity, anxiety and depression, burden of the disease and treatment and adherence to treatment, at days 180 and 360 after randomization in the two treatment groups, and during the long-term follow-up | 360 days | 
| Patient survival and quality of life | Number of patient survival | 360 days | 
| To assess renal outcome | A complete response is defined as a decrease in the proteinuria level to < 0.5 gm/ day (or urine protein-to-creatinine ratio <0.5 gm/gm), the disappearance of hematuria, and no decrease in the eGFR of more than 20% from baseline. | 360 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rituximab