A Randomized Open-label Study to Evaluate the Efficacy and Safety of Tacrolimus and Corticosteroids in Comparison With Mycophenolate Mofetil and Corticosteroids in Subjects With Class III/IV±V Lupus Nephritis
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 130
- 试验地点
- 1
- 主要终点
- Efficacy of combined corticosteroids and TAC compared to combined corticosteroids and MMF in achieving sustained renal response (RR) in patients with active lupus nephritis [Class III/IV±V (LN)]
研究概览
简要总结
Prospective, randomized, parallel-group controlled, open-label, international (Asian) multicenter, comparison of corticosteroids combined with tacrolimus and corticosteroids combined with mycophenolate mofetil.
详细描述
There is accumulating evidence that tacrolimus (TAC) could serve as an effective medication for the treatment of lupus nephritis (LN). TAC is a calcineurin inhibitor, which is a key component in first-line combination immunosuppressive regimens after kidney transplantation, based on its proven efficacy in the prevention and treatment of allograft rejection and acceptable tolerability profile. Although it primarily targets T lymphocyte activation, its immunosuppressive actions encompass multiple immune response pathways due to the complex interactions between different cellular and soluble immune mediators. Moreover, the effect of calcineurin inhibitors on podocyte morphology and function, independent of their immunosuppressive effect, has translated into therapeutic efficacy in the treatment of proteinuric glomerular diseases such as membranous nephropathy and focal segmental glomerulosclerosis. Recent data from short-term studies showed that combination immunosuppressive regimens that included TAC and corticosteroids with or without mycophenolate mofetil (MMF) appeared at least as effective as other standard-of-care treatments for Class III/IV±V LN, and the inclusion of TAC might lead to more effective suppression of proteinuria. There is also preliminary data on its favorable tolerability when used as long-term maintenance treatment. This study aims to examine the role of TAC combined with corticosteroids, in comparison with the most commonly used standard-of-care treatment MMF plus corticosteroids, in the management of lupus nephritis.
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
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Biopsy-proven LN Class III/IV±V (ISN/RPS 2003), with biopsy performed within 12 weeks of randomization.
- •Positive anti-dsDNA.
- •Active LN with proteinuria (urine protein/creatinine ratio ≥1.0 or 24-hr urine protein ≥1.0 g at baseline), with or without hematuria.
- •Both 'incident' (i.e. new) patients and 'flare' patients can be included.
- •Males or females aged 18 to 75 years inclusive at the time of screening.
排除标准
- •Renal disease unrelated to SLE (e.g. diabetes mellitus, other glomerular or tubulointerstitial disease, renovascular disease), or transplanted kidney.
- •Estimated glomerular filtration rate (eGFR by MDRD) ≤20 mL/min per 1.73 m2 or serum creatinine ≥300 micromol/L (3.39 mg/dL) at screening.
- •Renal biopsy showing cellular or fibrocellular crescent in more than 25% of glomeruli.
- •CNS or other severe organ manifestation of lupus that necessitate aggressive immunosuppressive therapy on its own.
- •Co-morbidities that require corticosteroid therapy (e.g. asthma, inflammatory bowel disease).
- •Treatment with prednisolone (or prednisone, or equivalent) at ≥20 mg/D for over 4 weeks within the past 3 months.
- •Treatment with MMF at >1.5 g/D for over 4 weeks within the past 3 months.
- •Known hypersensitivity or intolerability to prednisolone (or prednisone, or equivalent), TAC, or MMF at a dose of 1.25 g or below per day.
- •Subjects who are already on treatment with TAC, cyclosporine or any other calcineurin inhibitor on the day of screening; or have received treatment with TAC, cyclosporine or other calcineurin inhibitor for over 4 weeks within the past 6 months.
- •Treatment with cyclophosphamide, leflunomide, or methotrexate for over 2 weeks, or use of biological agent(s) regardless of duration, within the past 6 months (Note: prior use of azathioprine, mizoribine, intravenous immunoglobulins and anti-malarials is allowed).
- •Uncontrolled hypertension with systolic BP >160 mmHg or diastolic BP >95 mmHg.
- •Women who are pregnant or breastfeeding.
- •Women with childbearing potential or their male partners, who refuse to use an effective birth control method
研究组 & 干预措施
Tacrolimus
route: oral duration: 96 weeks
干预措施: Tacrolimus (Drug)
Mycophenolate Mofetil
route: oral duration: 96 weeks
干预措施: Mycophenolate mofetil (Drug)
结局指标
主要结局
Efficacy of combined corticosteroids and TAC compared to combined corticosteroids and MMF in achieving sustained renal response (RR) in patients with active lupus nephritis [Class III/IV±V (LN)]
时间窗: 96 weeks
Sustained RR defined as satisfying all of the following criteria: 1. proteinuria improved by ≥50% compared with baseline 2. 24-hr urine protein \<1 g 3. serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2 4. no occurrence of disease flare AFTER achieving response to treatment. Disease flare is defined as the need for 'rescue' immunosuppressive therapy with any one of the following i. increase of prednisolone dose from ≤7.5 mg/D to ≥15 mg/D for 4 weeks or longer ii. change of originally assigned immunosuppressive agent iii. addition of immunosuppressive medications prohibited in protocol
次要结局
- Rate of partial renal remission(96 weeks)
- Rate of complete renal remission(96 weeks)
- Efficacy of combined corticosteroids and TAC compared to combined corticosteroids and MMF in achieving sustained renal response (RR) in patients with active lupus nephritis [Class III/IV±V (LN)](48 weeks)
- Refractory disease(96 weeks)
- Rate of non-renal flare(96 weeks)
- Incidence of acute kidney injury(96 weeks)
- Incidence of new onset hypertension or worsening hypertensive control(96 weeks)
- Incidence of new onset hypercholesterolemia(96 weeks)
- Rate of treatment intolerance leading to premature study discontinuation(96 weeks)
- Rate of disease flare leading to premature study discontinuation(96 weeks)
- Incidence of adverse events(96 weeks)
- Incidence of TAC blood level above target range(96 weeks)
- Incidence of new onset diabetes mellitus(96 weeks)
- Rate of infection(96 weeks)
- Rate of Hospitalization(96 weeks)
- Incidence of hyperkalemia(96 weeks)
- Incidence of metabolic acidosis(96 weeks)
- Number of patients who failed to adhere to protocol defined corticosteroid reduction regimen(96 weeks)
- Rate of disease complication leading to premature study discontinuation(96 weeks)
- Changes in SFI scores(96 weeks)
- Incidence of serious adverse events(96 weeks)
- Changes in SELENA-SLEDAI scores(96 weeks)
- Changes in PGA scores(96 weeks)
- Changes in BILAG (2004) scores(96 weeks)
研究者
Professor Daniel Tak-Mao Chan
Professor
The University of Hong Kong