Rituximab and RASi in Patients With IgAN

Study Overview
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Brief Summary
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A study to evaluate safety and activity in treatment of IgAN patients using Rituximab in combination with RASi(ACEI and/or ARB) compared with RASi.

Detailed Description
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IgA nephropathy (IgAN, IgA nephropathy), is currently the most common glomerular disease worldwide, which is characterized by High population quantity, wide distribution, strong heterogeneity. Diagnosis of Urinary protein control level within 1 year is one of the important predictors of renal failure in IgAN patients.Previous studies have shown that patients with renal insufficiency, hypertension, or urinary protein > 1g at 24h during renal biopsy, and those with poor urinary protein control within 1 year of follow-up, have a higher risk of disease progression, and more than 30-50% of patients will develop into end-stage renal disease (ESRD) within 10 years. The recommended treatments for IgAN in the KDIGO guidelines include: RASi, glucocorticoid, immunosuppressor, antiplatelet drugs, lipid-lowering drugs, etc. Several trials have demonstrated the benefit of RASi in retarding disease progression in IgAN patients with proteinuria, but there is currently no specific treatment for IgAN. In recent years, it has been found that excessive production of Galactos-deficient IgA1 is one of the initiating factors of the pathogenesis of IgAN. Infection by pathogenic microorganisms induces lymphocytes in IgAN patients to produce anti-GD-IgA1 autoantibodies (second strike), which forms circulating immune complexes to deposit in the kidney and activates complement, which is an important pathogenesis of IgAN.However, recent studies have suggested that B-cell depletion therapy is effective for many aabs mediated renal diseases (e.g., membranous nephropathy, lupus nephritis, etc.). Rituximab, which combined with CD20 antigen on the B cell surface, can deplete B cells and play a therapeutic role by reducing antibody production. Therefore, the treatment of rituximab has potential therapeutic value for IgAN patients as well. However, there were very few studies which have shown the efficacy and safety of rituximab in the treatment of IgA nephropathy, only groups reported abroad, and the results were inconsistent. At present, there have been no randomized controlled studies to verify the safety and efficacy of rituximab in the treatment of IgA nephropathy, especially in Chinese with high incidence of IgAN. In this study, treatment of rituximab combining with RASi will be compared with RASi for IgAN patients, to explore an effective and safer regimen for IgAN, so as to bring more hope to patients.

Official Title
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A Multicentre, Randomized, Controlled Study of Rituximab in Treatment of Primary IgA Nephropathy

Conditions
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IgA Nephropathy

Intervention / Treatment
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* Drug: Rituximab
* Drug: RAS 2410


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. 18 to 75 of age, male or female; 2. primary IgA nephropathy confirmed by renal biopsy 3. eGFR>30ml/min/1.73m2(calculated according to the CKD-EPI formula); 4. After using maximum tolerated doses of ACEI and/or ARB for 3 months, the following two points should be met: 24h proteinuria ≥1g; Bp<130/80 mmHg； 5. Serum albumin > 25g/L; 6. Sign the informed consent. Note : It is suggested that active IgAN patients should be selected. Active IgAN is specifically defined as conforming to any of the following : ) intradermal augmentation ( E1 ), ) crescentic body 0 - 50 % ( C1 / C2 ), ) fibrinoid necrosis, ) more interstitial inflammatory cell infiltration. At the same time, the proportion of sclerosis was low ( spherical or segmental sclerosis ball < 50 % ), and interstitial fibrosis was low ( below T2 ). Exclusion Criteria: 1. Evidence of the use of glucocorticoids for immunosuppressive therapy, such as: nephrotic syndrome, pathology for small lesions with IgA nephropathy. or the proportion of crescents confirmed by renal biopsy within 12 months was more than 50 %. 2. Clinical confirmation of cirrhosis, chronic active liver disease, or hepatitis B, C, or HIV which can detect viral replication; 3. Clinically confirmed IgA nephropathy secondary to systemic diseases such as systemic lupus erythematosus, allergic purpura. 4. Patients with non-simple IgA nephropathy, such as diabetic nephropathy or obesity-related nephropathy. 5. A history of active systemic infection or severe infection occurred one month before enrollment. 6. Those who are pregnant or lactating or unwilling to take contraceptive measures. 7. Current or recent ( within 30 days ) exposure to any research drug. 8. Patients with allergic reactions to rituximab and / or known allergic reactions. 9. Laboratory tests meeting the following criteria should be excluded: (1) Hemoglobin <80g/L; (2) Platelet <80×10^9/L; (3) Neutrophils < 1.0×10^9/L; (4) Aspartic acid aminotransferase (AST) or alanine aminotransferase (ALT) >2.5× normal upper limit, except for the correlation with the primary disease; 10. Continuous use of hormones or other immunosuppressive therapy in the past 6 months; 11. Accompanying or past malignant tumors, except for fully treated skin basal or squamous cell carcinoma or cervical carcinoma in situ; 12. History of psychosis may interfere with normal participation in this study; 13. Patients with major heart or lung diseases (including obstructive pulmonary disease); 14. In acute and chronic tuberculosis infection period (tuberculin test positive, chest X-ray suspected tuberculosis patients); 15. Patients with history of immunodeficiency, including other acquired or congenital immunodeficiency diseases, or a history of organ transplantation; 16. Weight less than 50kg should be excluded; 17. Other researchers judge the patients unsuitable for inclusion in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab+RASi(ACEI and/or ARB)<br>The maximum tolerable dose of RASi will be using everyday depending on the individual factors of the subject, combined with rituximab 1g(D1, D31 respectively, intravenous infusion). Add 1 g rituximab at 6 months. | Drug: Rituximab<br>* To evaluate the efficacy and safety of HLX01 combined with RASi in patients with IgAN.<br>* Other names: HLX01;Drug: RAS 2410<br>* To evaluate the efficacy and safety of RASi in patients with IgAN.<br>* Other names: No specific restrictions;|
| Other: RASi(ACEI and/or ARB）<br>The maximum tolerable dose of RASi will be using everyday depending on the individual factors of the subject. | Drug: RAS 2410<br>* To evaluate the efficacy and safety of RASi in patients with IgAN.<br>* Other names: No specific restrictions;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in proteinuria levels over 1 year compared with baseline | Primary outcome included changes in proteinuria levels over 1 year compared with baseline | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of 50% reduction in mean urinary protein compared with baseline over 1 year | Statistical data of proportion of 50% reduction in mean urinary protein compared with baseline over 1 year | 1 year | 
| The proportion of 50% reduction in mean urinary protein compared with baseline over 6 months | Statistical data of proportion of 50% reduction in mean urinary protein compared with baseline over 6 months | 6 months | 
| Changes in proteinuria levels over 6 months compared with baseline | Secondary Outcome included changes in proteinuria levels over 6 months compared with baseline | 6 months | 
| Changes in eGFR levels over 1 year compared with baseline | To evaluate the efficacy of treatment in renal function | 1 year | 
| Changes in Gd-IgA1 levels | To observe the changes in GD-IGA1 level | 1 year | 
| Incidence of adverse events | Record the safety of Interventional drugs | 1 year | 
| Incidence of ESRD | Evaluate the efficacy of treatment | 1 year | 
| The proportion of 50% reduction in eGFR levels or doubling serum creatinine compared with baseline | To evaluate the renal function | 1 year | 
| Incidence of infection | To evaluate the safety of Rituximab | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IgAN, Rituximab, RASi, Gd-IgA1, proteinuria