Trial of Belimumab Combined With Multi-target Induction Therapy in Lupus Nephritis

Study Overview
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Brief Summary
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The goal of this single-center, prospective clinical trial is to test the safety and efficacy of belimumab combined with multi-target therapy in the treatment of severe lupus nephritis. The main questions it aims to answer are: lupus nephritis complete remission rate at week 24, and the partial remission rate and safety assessments. Patients with severe lupus nephritis will be enrolled and received pulse methylprednisolone at a dose of 1.5 to 3.0g, followed by intravenous belimumab at a dose of 10mg per kilogram at weeks 2, 4, and 6, and every 4 weeks thereafter. Multitarget therapy will be also administered during the induction phase. Induction therapy will last for 24 weeks. Patients with severe lupus nephritis who only received multi-target therapy during the same period will be enrolled as the control group.

Official Title
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Clinical Trial of Belimumab Combined With Multi-target Induction Therapy in Adult Patients With Severe Lupus Nephritis

Conditions
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Lupus Nephritis, Remission, Safety Issues

Intervention / Treatment
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* Drug: Methylprednisolone Injectable Suspension
* Drug: Belimumab Injection
* Drug: Immunosuppressive Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active LN in accordance with the American College of Rheumatology (ACR) diagnostic criteria for SLE (1997), SLE-DAI>10 points (except type Ⅴ LN). Patients with active lupus nephritis (type Ⅲ, Ⅳ, Ⅴ, Ⅴ+Ⅲ, Ⅴ+Ⅳ) diagnosed by light microscopy, immunofluorescence microscopy, and electron microscopy according to the ISN/RPS2003 lupus nephritis classification criteria, with pathological chronicity index (CI) less than 3 points and no TMA like changes in interstitial vessels. Proteinuria ≥1.5g/24h, with or without active urinary sediment (urinary sediment red blood cell count >100/ul, or white blood cell count >5 /HP, or red blood cell cast, excluding urinary tract infection). Serum creatinine <3.0mg/dL or eGFR<30 ml/min/1.73m^2 (CKD-EPI formula). Received methylprednisolone pulse therapy within 2 weeks before enrollment, cumulative dose 1.5-3.0g). Exclusion Criteria: Required renal replacement therapy or received renal replacement therapy within 3 months. Abnormal liver function with elevated ALT, AST or bilirubin more than 2 times the upper limit of normal. Abnormal glucose metabolism, defined as fasting blood glucose concentration ≥7.0mmol/L and/or 2-hour postprandial blood glucose concentration >11.1mmol/L. Mycophenolate mofetil, cyclophosphamide, tacrolimus, cyclosporine A, and high-dose intravenous immunoglobulin (IVIG) were used in the past 12 weeks; It did not include oral hormones, azathioprine or tripterygium wilfordii polyglycosides, or intravenous low-dose MP (less than 80mg/ day), or short-term use of cyclosporine A<2 weeks, or leflunomide <4 weeks. Known allergy to or contraindication to MMF, tacrolimus, or belimumab; Patients with active infection or intravenous antibiotic use within 1 month before admission. Current or past 3 months: active hepatitis B, hepatitis C, tuberculosis, cytomegalovirus pneumonia, active fungal infection, syphilis infection or HIV infection, etc.; Active peptic ulcer; A history of drug use and alcohol abuse; Severe malnutrition (BMI<16 kg/m^2). Other active diseases, such as severe life-threatening cardiovascular diseases; Chronic obstructive pulmonary disease, or asthma requiring treatment with oral steroids; Bone marrow suppression caused by SLE activity was excluded: WBC<3000/ul, absolute neutrophil count <1300/ul, and platelet count < 50 000/ul. Patients with active SLE who received double plasma filtration, plasma exchange or high-dose gamma globulin therapy within 4 weeks. Patients with malignant hypertension. Women who have fertility requirements, refuse contraception or are lactating. Other investigators considered that they were not suitable for enrollment and may have rapid disease progression or severe disease complications.

Ages Eligible for Study
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Minimum Age: 14 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Belimumab and multi-target therapy group<br>Patients with severe lupus nephritis will be enrolled and received pulse methylprednisolone at a dose of 1.5 to 3.0g, followed by intravenous belimumab at a dose of 10mg per kilogram at weeks 2, 4, and 6, and every 4 weeks thereafter. Multitarget therapy will be also administered during the induction phase. Induction therapy will last for 24 weeks. | Drug: Methylprednisolone Injectable Suspension<br>* Methylprednisolone pulse therapy, total dose from 1500mg to 3000mg.<br>* Other names: Methylprednisolone pulse therapy;Drug: Belimumab Injection<br>* Belimumab at a dose of 10mg per kilogram at weeks 2, 4, and 6, and every 4 weeks for 24 weeks.<br>* Other names: Beliumab induction therapy;Drug: Immunosuppressive Agents<br>* Mycophenolate Mofetil, oral, 1.0-1.5g per day; Tacrolimus, oral, 2-4mg per day.<br>* Other names: Multi-target immunosuppressive therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a cumulative complete response at week 24 of treatment. | Complete response will be defined as below: urinary protein less than 0.4g/24h no active urinary sediment serum albumin more than 3.5g/dl and normal SCr. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with partial response and non-response to treatment. | Partial response will be defined as a decrease of more than 50% of the baseline value of urinary protein and less than 3.5g/24h of urinary protein, a decrease of more than 50% of the baseline value of urinary sediment red blood cell count, and a normal or an increase of less than 30% of serum creatinine | 24 weeks | 
| Overall response rate at 24 weeks. | These will include complete remission and partial remission | 24 weeks | 
| Improvement of clinical indicators. | Clinical improvement of the disease was assessed using systemic lupus erythematosus disease activity index. | 24 weeks | 
| The changes of B cells. | The changes of CD20 number in peripheral blood will be observed and investigated. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lupus nephritis, B cell depletion therapy, Remission