Induction Therapy for Lupus Nephritis With no Added Oral Steroids: An Open Label Randomised Multicentre Controlled Trial Comparing Oral Corticosteroids Plus Mycophenolate Mofetil (MMF) Versus Obinutuzumab and MMF
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 196
- 试验地点
- 1
- 主要终点
- Proteinuria measurement
研究概览
简要总结
This is a randomised, open label, controlled non-inferiority phase III multicentre trial.
As primary objective, the study aims to demonstrate that a regimen free of additional oral corticosteroids but with obinutuzumab (and MMF) is non-inferior to a regimen based on oral corticosteroids and MMF in achieving the primary outcome of complete renal response at week 52 without receiving corticosteroids above a prespecified dose.
As secondary objectives, the study aims:
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To compare the efficacy of the treatments in both arms in terms of:
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partial plus complete renal response at week 52;
-
proteinuria < 0.8g/g at week 52;
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extrarenal flares;
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response as defined by a >4 points reduction in SELENA-SLEDAI score at week 52.
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To compare the safety of the treatments in both arms in terms of occurrence of:
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toxicity of corticosteroids;
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serious Adverse Events;
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serious Infectious Episodes;
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new damage.
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To compare the number of patients with non-adherence to treatment in both arms.
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To estimate the efficiency of obinutuzumab in this indication.
The ancillary studies will allow:
- To implement a biobank (serum, plasma, DNA, cells and urine) and a bank of renal biopsies for studies that will be part of separate research funding bids (patients will be informed that their samples and data may be used for subsequent studies and offered to consent or not).
- To identify which target therapeutic levels of MMF best predicts response with least toxicity (ancillary study).
- To have long term data on renal function and damage.
详细描述
Preliminary data show that the anti CD20 monoclonal antibody may effectively replace oral corticosteroids in the induction treatment of lupus glomerulonephritis. The concept of avoiding significant use of corticosteroids would mark a step change in the approach to the treatment of lupus nephritis but the efficacy of such a strategy first needs to be confirmed in a randomised controlled study.
The main aim of this study is to demonstrate that patients with lupus nephritis could be treated successfully without using damaging doses of oral corticosteroids.
Eligible patients will be randomised with 1:1 ratio, between interventional group (obinutuzumab, IV methylprednisolone, no or low dose corticosteroids and MMF) and control group (oral prednisone, IV methylprednisolone and MMF), after signed informed consent obtaining. Randomization will be blocked and stratified by level of proteinuria (<1 g/g versus ≥ 1 g/g). Previous 52 centers will participate to the trial.
Study assessments will occur on a standard of care basis at 15 days, 1, 3, 6, 9 and 12 months (and at any flare or according to the wishes of the investigator). Study assessment will include assessment of disease activity, disease- and treatment-related damage, quality of life, and blood and urine tests as standard of care. In addition, a biobank will be sampled at inclusion. Long-term data on damage and renal function will be collected during standard of care (18 months, 2, 5 and 10 years) in patients who consented.
Population involved: Children (14 years and above) and adults with lupus nephritis ISN/RPS class III or IV (A or A/C) ± V with active lesions in at least 10% of the viable glomeruli, AND urine protein-to-creatinine ratio (uPCR) ≥ 0.5 g/g.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children aged 14-17 years old and adults;
- •Active lupus nephritis, as defined by kidney biopsy within the preceding 8 weeks, assessed by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification: class III or IV (A or A/C) ± V with active lesions in at least 10% of the viable glomeruli;
- •Urine protein-to-creatinine ratio (uPCR) ≥ 0.5 g/g at any time in the 14 days before inclusion;
- •No contraindications to the use of IV methylprednisolone, MMF, oral corticosteroids or obinutuzumab;
- •Ability to provide informed consent;
- •Willingness to use appropriate contraception, as recommended when using MMF.
排除标准
- •Severe "critical" SLE flare defined as any SLE manifestation requiring more immunosuppression than allowed in the protocol, in the physician's opinion;
- •Patients who cannot be prescribed 10 mg prednisone corticosteroids "only", after inclusion according to the physician's opinion;
- •Pregnant and breastfeeding woman;
- •Prior use within 6 months of inclusion of therapeutic monoclonal antibody and/or B- or T cell modulating 'biologic' except belimumab that can be used up to 7 days before inclusion;
- •Obsolescence of >60% of the glomeruli or tubulointerstitial scarring of >60%;
- •CKD stage 4 or stage 5 defined as eGFR <30 ml/min/1.73 m2 according to CKD-EPI (to be differentiated from acute renal injury);
- •Active infections, including but not limited to human immunodeficiency virus (HIV), hepatitis B in the absence of a specific therapy, hepatitis C or tuberculosis;
- •Receipt of a live-attenuated vaccine in the 4 weeks prior to study enrolment;
- •History of cervical dysplasia CIN Grade III, cervical high-risk human papillomavirus or abnormal cervical cytology other than abnormal squamous cells of undetermined significance (ASCUS) in the past 3 years in female patients. However, the patient will be eligible in the following conditions: follow-up HPV test is negative or cervical abnormality was effectively treated >1 year ago.
研究组 & 干预措施
Obinutuzumab arm
Obinutuzumab administration plus oral mycophenolate mofetil (MMF)
干预措施: Administration of methylprednisolone, paracetamol and dexchlorpheniramine (Drug)
Obinutuzumab arm
Obinutuzumab administration plus oral mycophenolate mofetil (MMF)
干预措施: Obinutuzumab administration (Drug)
Corticosteroids arm
Oral corticosteroids plus MMF
干预措施: Administration of Methylprednisolone + Prednisone + Mycophenolate mofetil (Drug)
结局指标
主要结局
Proteinuria measurement
时间窗: at week 52
Proteinuria measurement: the proteinuria/creatinuria ratio will be assessed on a 24-hour urine collection.
Complete renal response (CR)
时间窗: at week 52
CR at week 52 without receiving corticosteroids above a prespecified dose. CR at week 52 is defined as: * Urine PCR (protein to creatinine ratio) \< 0.5 g/g in a spot urine AND: * eGFR (estimated glomerular filtration rate using CKD-epi) ≥ 60 ml/min, or if \< 60 ml/min at screening, no decline \>20% compared to screening/randomisation (whichever worse) * AND: * In the obinutuzumab arm: with no steroids or without receiving oral corticosteroids \> 10 mg/day within the first 6 month, and then, without receiving oral corticosteroids \> 7.5 mg/day between 6 and 9 months and \> 5 mg/day between 9 and 12 months for SLE indication (according to the French PNDS for SLE after 6 months). * In the steroid arm: without receiving corticosteroids above the prescribed taper (according to the French PNDS for SLE, see Appendix A), including without receiving oral corticosteroids \> 7.5 mg/day between 6 and 9 months and \> 5 mg/day between 9 and 12 months for SLE indication (according to the French
次要结局
- Efficacy: proteinuria measurement(at baseline and at week 52)
- Safety: toxicity of corticosteroids measurement(at inclusion, at Month 6 and Month 12)
- Safety: serious adverse events (SAE) report(through study completion, an average of 10 years)
- Safety: number of serious infectious episodes(through study completion, an average of 10 years)
- Safety: changes in the SLICC/ACR damage index.(at inclusion, at Month 6 and Month 12)
- Non-adherence to treatment: hydroxychloroquine blood levels(at Month 6 and Month 12)
- Non-adherence to treatment: questionnaires MASRI(at Month 6 and Month 12)
- Efficiency(at one year)
- Efficacy: complete renal response(at baseline and at week 52)
- Efficacy: partial renal response (PR)(at baseline and at week 52)
- Efficacy: extrarenal flare(at baseline and at week 52)
- Efficacy: changes in the SELENA-SLEDAI score(at baseline and at week 52)