Clinical Study of Rituximab Combined With Corticosteroids or Rituximab Monotherapy in the Treatment of Primary Membranous Nephropathy

Official title

A Prospective, Randomized, Multicenter Clinical Trial Comparing the Efficacy and Safety of Rituximab Combined With Corticosteroids or Rituximab Monotherapy in Primary Membranous Nephropathy

Overview

This was a prospective, randomized, multicenter clinical trial. Seventy-eight patients with primary membranous nephropathy (PMN) were randomly divided into intervention or control group. Intervention group was given rituximab combined with corticosteroids in induction therapy and the control group was given rituximab monotherapy. After 6 months, patients who had decreased 24h urinary protein by \> 25% but did not achieve CR were given rituximab maintenance therapy. The complete response rate at 12 months was measured.

Detailed description

Study design A prospective, randomized , multicenter clinical study

Outcomes

* Primary objective To evaluate the efficacy of rituximab combined with corticosteroids or rituximab monotherapy in primary membranous nephropathy * Secondary Objectives The safety of rituximab combined with corticosteroids or rituximab monotherapy in primary membranous nephropathy;

Primary outcome The complete response rate at 12 months;

* Secondary outcomes

1. Response rates at 6, 12, 18 and 24 months (including the proportion of participants with complete response and partial response); 2. Median remission time; 3. Proportion of patients without recurrence at 12, 18 and 24 months; 4. Median non-recurrence time; 5. Cumulative dose of glucocorticoids; 6. CD19+ cell count, anti-PLA2R antibody expression level; 7. Renal function index: eGFR; 8. Incidence of adverse events;

Study population Seventy-eight male or female treatment-naïve primary membranous nephropathy (PMN) patients

Description of the study intervention Intervention group: rituximab combined with corticosteroids: 39 cases. Patients are pretreated with diphenhydramine and dexamethasone 30-60 minutes before rituximab infusion. * Induction therapy:

Rituximab intravenous infusion of 1g, d1, d15, combined with glucocorticoid therapy, oral prednisolone, initial dose of 0.5mg/(kg·d), once a day, after 8 weeks of treatment, reduce by 5mg every 4 weeks until 0.25mg/kg, this dose was maintained for 8 weeks, and then reduced by 2.5mg every 4 weeks, until 5-10mg is maintained, and the total course of treatment was about one year or so;

\- Consolidation therapy after 6 months: Patients who achieve CR do not require consolidation therapy; Patients who had a 24-hour reduction in proteinuria \>25% but did not achieve CR received an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count).

Patients with less than 25% decrease in proteinuria in 24 hours do not require continued medical therapy, and were considered as treatment failure and withdraw from the trial.

Control group: Rituximab monotherapy: 39 cases,

\- Treatment regimen: 30-60 minutes before intravenous infusion of rituximab, diphenhydramine 20mg intramuscularly and dexamethasone 5mg intravenously were given for pretreatment.

* Induction therapy:Rituximab intravenous infusion of 1g, d1, d15 * Consolidation therapy after 6 months:

Patients who achieve CR do not require consolidation therapy; Patients who had a 24-hour reduction in proteinuria \>25% but did not achieve CR received an additional course of rituximab 1g, D1, D15 (independent of CD19+ cell count).

Patients with less than 25% decrease in proteinuria in 24 hours do not require continued medical therapy, and were considered as treatment failure and withdraw from the trial.

The duration of the entire clinical study was 36 months from the date of project initiation.

Duration of visits: 2 years

Interventions

• Drug rituximab combined with corticosteroids
  Induction therapy: Rituximab intravenous infusion of 1g, d1, d15, combined with glucocorticoid therapy, oral prednisolone, initial dose of 0.5mg/(kg·d), once a day, after 8 weeks of treatment, reduce by 5mg every 4 weeks until 0.25mg/kg, this dose was maintained for 8 weeks, and then reduced by 2.5mg every 4 weeks, until 5-10mg is maintained, and the total course of treatment was about one year or so;
• Drug rituximab
  Control group (treated with Rituximab monotherapy treatment) :Rituximab intravenous infusion of 1g, d1, d15

Primary outcome measures

• The complete response rate at 12 months; [Time frame: 12 months]

Secondary outcome measures (8)

• Response rates at 6, 12, 18 and 24 months (including the proportion of participants with complete response and partial response); [Time frame: 24 months]
• Median remission time; [Time frame: 24 months]
• Proportion of patients without recurrence at 12, 18 and 24 months; [Time frame: 24 months]
• Median non-recurrence time; [Time frame: 24 months]
• Cumulative dose of glucocorticoids; [Time frame: 24 months]
• CD19+ cell count, anti-PLA2R antibody expression level; [Time frame: 24 months]
• Renal function index: eGFR; [Time frame: 24 months]
• Incidence of adverse events; [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Men and women aged 18-75 years;
• Patients diagnosed as primary membranous nephropathy (PMN) by renal biopsy;
• After treatment with ACE inhibitors or ARBs for at least 3 months, the following two points were met (unless intolerance to ACE inhibitors or ARBs, contraindications, hypotension that may cause side effects, or the investigator judged that the patient was not suitable for RAS inhibitors):

(1) Those who have an average 24-hour urine protein ≥ 3.5g twice a week, or an average 24-hour urine protein ≥ 5g twice in 14 days, the requirement of RASi for at least 3 months is not required (2) Blood pressure≤ 130/80mmHg, 4. Glomerular filtration rate (eGFR) ≥30mL/min/1.73m2 (calculated according to the CKD-EPI formula) 5. If female, must be postmenopausal or postoperatively infertile or on medical contraception (considering the potential risk of thromboembolism in patients with kidney disease); 6. Subjects voluntarily signed the informed consent form;

Exclusion criteria

• Patients with type 1 diabetes mellitus or type 2 diabetes mellitus complicated with diabetic nephropathy. Patients with a recent history of steroid-induced diabetes were eligible if renal biopsies show no evidence of secondary diabetic nephropathy within 6 months before the screening period
• Patients with secondary membranous nephropathy (such as hepatitis B and C, systemic lupus erythematosus, drug therapy, malignant tumors and other secondary causes);
• Previous treatment with rituximab, steroids, alkylating agents, calcineurin inhibitors, synthetic ACTH, mycophenolate (MMF), and azathioprine;
• Receipt of any other study medication (within the last month);
• Suspected or known allergy or immune reaction to rituximab, corticosteroids or any of their components (including excipients);
• Active infection, such as active hepatitis B or hepatitis C, tuberculosis (evidence of active tuberculosis infection within 1 year), or human immunodeficiency virus HIV infection (positive for anti-HIV antibodies), etc.
• A history of immunodeficiency, including other acquired or congenital immunodeficiency diseases, or organ transplantation;
• Females with a positive pregnancy screening test or lactating or planning to become pregnant in the next 24 months. Female or male patients who were unwilling to use contraceptive methods throughout the study;
• A history of mental illness;
• Laboratory tests that meet the following criteria need to be excluded:

(1) Hemoglobin<80g/L; (2) Platelet < 80×109/L; (3) Neutrophil <1.0×109/L; (4) Aspartate aminotransferase (AST) or amino aminotransferase (ALT) > 2.5× upper limit of normal except in relation to the primary disease; 11. Very high-risk patients: presenting with life-threatening nephrotic syndrome, or unexplained rapid deterioration of renal function 12. Any patient judged by the investigator to be unsuitable for inclusion in the trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Wei Chen — Guangzhou

Publications

• Cai Q, Hendricks AR. Membranous nephropathy: A ten-year journey of discoveries. Semin Diagn Pathol. 2020 May;37(3):116-120. doi: 10.1053/j.semdp.2020.01.001. Epub 2020 Jan 29. PMID 32061439
• Pathological features and diagnosis of membranous nephropathy
• Dahan K. [Membranous nephropathy: Diagnosis, new insights in pathophysiology, and therapeutic approach]. Rev Med Interne. 2016 Oct;37(10):674-679. doi: 10.1016/j.revmed.2016.02.003. Epub 2016 May 25. French. PMID 27236434
• Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2;361(1):11-21. doi: 10.1056/NEJMoa0810457. PMID 19571279
• Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pelle T, Gaspari F, Suardi F, Gagliardini E, Orisio S, Benigni A, Ronco P, Remuzzi G. Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy. J Am Soc Nephrol. 2015 Oct;26(10):2545-58. doi: 10.1681/ASN.2014070640. Epub 2015 Mar 24. PMID 25804280
• Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4S):S1-S276. doi: 10.1016/j.kint.2021.05.021. No abstract available. PMID 34556256
• Expert consensus on the use of rituximab in glomerulonephritis
• Expert Group on Biologics Treatment of Immune Glomerular Diseases. Chinese Expert Consensus on Biologics for the Treatment of Immune Glomerular Diseases.

Identifiers

NCT: NCT05514015 · HLK-202302

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗