Rituximab and RASi in Patients With IgAN (RITA)

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

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.

Study Overview

• Status: Recruiting
• Conditions: IgA Nephropathy
• Intervention / Treatment: Drug: Rituximab; Drug: RAS 2410

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 116
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nan Chen; Phone Number: +86 13601638963; Email: cnrj100@126.com
• Study Contact Backup: Name: Jingyuan Xie; Phone Number: +86 13761056656; Email: nephroxie@163.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Ruijin Hospital, Shanghai Jiaotong University School of Medicine
      • Contact: Nan Chen; Phone Number: 13601638963; Email: cnrj100@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. 24h proteinuria ≥1g;
  2. 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 :

1. ) intradermal augmentation ( E1 ),
2. ) crescentic body 0 - 50 % ( C1 / C2 ),
3. ) fibrinoid necrosis,
4. ) 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab+RASi(ACEI and/or ARB); 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; To evaluate the efficacy and safety of HLX01 combined with RASi in patients with IgAN.; Other Names: HLX01; Drug: RAS 2410; To evaluate the efficacy and safety of RASi in patients with IgAN.; Other Names: No specific restrictions
Other: RASi(ACEI and/or ARB）; The maximum tolerable dose of RASi will be using everyday depending on the individual factors of the subject.	Drug: RAS 2410; To evaluate the efficacy and safety of RASi in patients with IgAN.; Other Names: No specific restrictions

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: CHENNAN
• Collaborators: Third Affiliated Hospital, Sun Yat-Sen University; Sir Run Run Shaw Hospital; Shanghai Pudong New Area People's Hospital; Dongfang Hospital Affiliated to Tongji University; Ruijin Hospital North Shanghai Jiao Tong University School of Medicine; Ningbo Municipal Yinzhou District No.2 Hospital; Xiamen Hongai Hospital
• Investigators: Principal Investigator: Jingyuan Xie, Ruijin Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: August 17, 2020
• First Submitted That Met QC Criteria: August 22, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: proteinuria; Rituximab; IgAN; RASi; Gd-IgA1
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Kidney Diseases; Glomerulonephritis, IGA; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: RITA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No