Efficacy and Safety of the Treatment of Primary Membranous Nephropathy: A Randomized Clinical Trial

Efficacy and Safety of Rituximab Combined With Tacrolimus in the Treatment of Intermediate-to-high Risk Primary Membranous Nephropathy: A Randomized Clinical Trial

1. Main purpose:

   To evaluate the efficacy and safety of rituximab combined with tacrolimus in the treatment of intermediate and high-risk primary membranous nephropathy

2. Secondary research purposes:

   To describe the survival of patients with intermediate and high-risk primary membranous nephropathy treated with rituximab combined with tacrolimus; To describe renal survival in patients with intermediate and high-risk primary membranous nephropathy treated with rituximab combined with tacrolimus;

3. Exploratory research purposes:

Feasibility of glucocorticoids-free therapy (rituximab combined with tacrolimus) in the treatment of intermediate and high-risk primary membranous nephropathy

Study Overview

• Status: Not yet recruiting
• Conditions: Efficacy and Safety
• Intervention / Treatment: Drug: Rituximab combined with tacrolimus induction + rituximab maintenance; Drug: Rituximab combined with tacrolimus induction + tacrolimus maintenance; Drug: Glucocorticoid combined with cyclophosphamide induction + maintenance

Detailed Description

Membranous nephropathy (MN) is the leading cause of primary nephrotic syndrome in adults, with a peak incidence in middle-aged and elderly patients. The typical pathological features are: thickening of the basement membrane, deposition of immunofluorescent IgG with or without C3 along the basement membrane, and deposition of epithelial electron-dense deposits. It is divided into primary MN (Primary membranous nephropathy, PMN) and secondary MN (which can be secondary to connective tissue diseases, infections, malignant tumors, drugs/toxicants, etc.). Clinically, it usually presents with massive proteinuria and edema, and some patients gradually progress to end stage renal disease (ESRD).

In recent years, the prevalence of PMN in China has increased year by year. It has been reported that the proportion of MN in primary glomerular diseases in renal biopsy increased from 10.4% in 2003-2006 to 24.1% in 2011-2014 [1], and some trend of youth.

For a long time, the treatment of PMN has mainly used glucocorticoids combined with alkylating agents or calcineurin inhibitors (CNIs). With the continuous exploration and in-depth understanding of the pathogenesis of MN, it has been developed to the molecular level. The KDIGO 2021 Glomerular Disease Management Guidelines are being published [2] Compared with the 2012 KDIGO Glomerular Disease Management Guidelines, the diagnosis and treatment of MN has undergone major changes (Figure 1). Due to the toxicity of alkylating agents and the long-term nephrotoxicity of CNIs, as well as their high risk of relapse when used as monotherapy (with or without prednisone), anti-CD20 biotherapeutics (especially Rituximab, RTX)) is gaining popularity as first-line therapy.

Both international and domestic guidelines recommend that moderate and severe MN require immunosuppressive therapy. RTX is an anti-CD20 monoclonal antibody, which can block the generation of B cells, differentiate into plasma cells, reduce the production of antibodies (such as PLA2R), and avoid processes such as glomerular basement membrane damage. TAC is a calcineurin inhibitor that has been used in PMN for many years. It mainly acts through various mechanisms such as immune regulation and stabilization of the pod cytoskeleton. Two-drug sequential therapy can work from multiple mechanisms, potentially achieving better and faster therapeutic effects.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Qin Wang, doctor; Phone Number: +86136 2196 4604; Email: qinwang_1975@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• gender is not limited；
• Age 18-75；
• Kidney biopsy pathology suggests primary membranous nephropathy;
• Serological or histological PLA2R positive;
• 24-hour urine protein quantification ≥3.5g/d and serum albumin <30g/L;
• Glomerular filtration rate [eGRF (CKD-EPI formula)] ≥ 45ml/min/1.73m2;

Exclusion Criteria:

• Secondary membranous nephropathy (tumor-related, lupus-related, hepatitis B-related, infection-related, drug-related, etc.);
• Renal biopsy pathology showed severe tubulointerstitial lesions;
• Severe infection, severe cardiac insufficiency, severe hepatic insufficiency, gastrointestinal bleeding, ketoacidosis and other life-threatening complications within one month;
• Glucocorticoids and/or immunosuppressive therapy (cyclophosphamide, MMF, tacrolimus) within 3 months;
• Have a history of kidney transplantation;
• Breastfeeding or pregnant women;
• Patients with mental disorders or unable to cooperate ;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RT-R Group; Rituximab combined with tacrolimus induction + rituximab maintenance	Drug: Rituximab combined with tacrolimus induction + rituximab maintenance; RT-R group: Rituximab 1 g/time, once in 15 days, × 2 times, combined with tacrolimus, the initial dose is 0.05-0.1 mg/kg/d, 2 times at an interval of 12 hours, orally. Adjust the dose according to the blood concentration (maintain the blood concentration C0 4-8ng/ml). At the end of 24 weeks, tacrolimus was stopped, and rituximab was given 1 g/time × 1 time.
Experimental: RT-T Group; Rituximab combined with tacrolimus induction + tacrolimus maintenance	Drug: Rituximab combined with tacrolimus induction + tacrolimus maintenance; RT-T group: Rituximab 1 g/time, once in 15 days, × 2 times, combined with tacrolimus, the initial dose is 0.05-0.1 mg/kg/d, 2 times at an interval of 12 hours, orally. Adjust the dose according to the blood concentration (maintain the blood concentration C0 4-8ng/ml).
Experimental: PC-C Group; Glucocorticoid combined with cyclophosphamide induction + maintenance	Drug: Glucocorticoid combined with cyclophosphamide induction + maintenance; PC-C group: The initial dose of prednisone/prednisolone was 0.5-1 mg/kg/d (the maximum dose was 70 mg/d), and the dose was gradually reduced after 4-8 weeks, and then stopped within 6-9 months. Cyclophosphamide 750mg/m2 (adjusted according to eGFR and other conditions), once a month, intravenous pulse therapy. CTX maintenance therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
24-hour urine protein quantification	Remission: decreased proteinuria. Complete remission (CR): 24HUTP<0.3g/L Partial remission (PR): 24HUTP decreased by >50% and >0.3g/L from baseline; Invalid: no decrease in proteinuria compared with baseline.; Recurrence: increased proteinuria (24-hour urine protein quantification ≥3.5g/d) , recurred after reaching CR or PR.	48 weeks
serum albumin	Remission: serum albumin>30g/L; Invalid: serum albumin <30g/L; Recurrence: decreased serum albumin, <30g/L, recurred after reaching CR or PR.	48 weeks

Collaborators and Investigators

• Sponsor: RenJi Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2022
• Primary Completion (Anticipated): September 30, 2023
• Study Completion (Anticipated): September 30, 2024

Study Registration Dates

• First Submitted: September 1, 2022
• First Submitted That Met QC Criteria: September 3, 2022
• First Posted (Actual): September 8, 2022

Study Record Updates

• Last Update Posted (Actual): September 8, 2022
• Last Update Submitted That Met QC Criteria: September 3, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Rituximab; Tacrolimus; Primary Membranous Nephropathy
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Kidney Diseases; Glomerulonephritis, Membranous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Calcineurin Inhibitors; Cyclophosphamide; Rituximab; Tacrolimus; Glucocorticoids
• Other Study ID Numbers: IIT-2021-0149

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No