A Pilot Study of Sirolimus in Treatment of Proteinuric Flares of Lupus Nephritis
试验速览
- 阶段
- 2 期
- 入组人数
- 20
- 主要终点
- The number of patients achieving sustained Renal Response(RR)
研究概览
简要总结
This a single-centre, one-arm, open-label pilot study. Eligible patients with mild proteinuric flares of lupus nephritis Class III/IV±V are received sirolimus without changing previous immunosuppressive medication during 12-week follow-up.
Primary Objective:
- To investigate the efficacy of sirolimus for mild proteinuric flares in patients with Class III/IV±V lupus nephritis
Secondary Objective:
- To assess the safety and tolerability of sirolimus treatment for mild proteinuric flares in patients with Class III/IV±V lupus nephritis
详细描述
Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE). It often requires aggressive immunosuppressive therapy. Although majority of patients with severe lupus nephritis achieve a complete or partial remission after 6-month induction treatment, renal flares can still occur during maintenance therapy. Whether patients with mild proteinuric flares should receive intensive immunosuppressive therapy is unclear. In pathogenesis of SLE, T-cell dysfunction is attributed to the activation of the mammalian target of rapamycin (mTOR). Previous prospective and retrospective studies in SLE or lupus nephritis showed the effect of mTOR blockade on systemic disease activity index or severe lupus nephritis as initial or maintenance therapy.
Eligible subjects with biopsy-proven Class III/IV±V lupus nephritis(ISN/RPS 2003) are received oral sirolimus without change previous immunosuppressive therapy. We follow up the included patients at Week 2, Week 4, Week6, Week 8 and Week 12 regularly.
The investigator will actively detect and inquire about the occurrence of adverse events (AEs)/ severe adverse events (SAEs) at every visit/ contact during the study. The clinical trials insurance is prepaid by sponsor to cover the design risks of the protocol and liability/ compensation to the research subject for bodily injury or death resulting from their participation in the trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Biopsy-proven Class III or IV±V lupus nephritis (ISN/RPS 2003 lupus nephritis classification) with biopsy performed within 48 weeks before inclusion.
- •Males or females aged 18 to 60 years old at the time of screening.
- •The mild proteinuric flare of lupus nephritis is defined as meeting all of the following criteria :
- •Persistently increased proteinuria after complete remission, and 24-hr proteinuria≥1.0g/day or doubling of proteinuria after partial remission, and 24-hr proteinuria≥2.0g/day
- •No hypoalbuminemia: serum albumin ≥35g/L
- •Stable renal function: serum creatinine<25% increase above the level at the time of renal disease remission
- •Eligible to sign informed-consent independently
排除标准
- •Renal disease unrelated to SLE (e.g. diabetes mellitus, other glomerular or tubulointerstitial diseases, renovascular disease), or transplanted kidney
- •Estimate glomerular filtration rate (eGFR by CKD-EPI)<45mL/min per 1.73m^2 at the time of screening
- •Renal biopsy showing cellular of fibrocellular crescent in more than 25% of glomeruli
- •Central nervous system (CNS) or other severe organ manifestations of lupus that necessitate aggressive immunosuppressive therapy on its own.
- •Co-morbidities that require corticosteroid therapy (e.g. asthma, inflammatory bowel disease)
- •Any increased dose of corticosteroids or other immunosuppressive medication including cyclophosphamide, mycophenolate, leflunomide, calcineurin inhibitors, azathioprine, methotrexate, or use of biological agents regardless of duration, with the past six months
- •Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection history: seropositivity of HBV surface antigen (HBsAg) or HCV antibodies (HCV-Ab)
- •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
Sirolimus group
- The initial dose of sirolimus is 1mg/day. And the serum trough level of sirolimus is monitored at Week 2, Week 4, Week 8, and Week 12，respectively. The target serum trough level of sirolimus is 5-8 ng/mL. The dose of sirolimus is titrated according to therapeutic drug level monitoring.
- The previous immunosuppressive medication is not allowed to be changed during the 3-month follow-up, unless premature discontinuation from study.
干预措施: Sirolimus (Drug)
结局指标
主要结局
The number of patients achieving sustained Renal Response(RR)
时间窗: at the end of 12 weeks (3 months) from baseline
Sustained RR is defined as satisfying all of the following criteria: 1)Proteinuria is improved by ≥50% compared with baseline 2)24-hr urine protein \< 1g 3)Serum creatinine is not higher than 15% above baseline level 4)No occurrence of non-renal disease flare after achieving response to treatment.
次要结局
- Increase of serum creatinine level>15% from baseline(during the 3-month follow up)
- Complete renal remission(at the end of 12 weeks (3 months) from baseline)
- Rate of non-renal flare(during the 3-month follow up)
- Changes in Physician Global Assessement (PGA)(from baseline to end of 12 weeks)
- Partial renal remission(at the end of 12 weeks (3 months) from baseline)
- Safety and tolerability of study medications(during the 3-month follow up)
- Failure to adhere to the protocol(during the 3-month follow up)
- Changes in Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI)(from baseline to end of 12 weeks)
- Episodes with sirolimus level above the target range(during the 3-month follow up)
- New-onset hypertension or worsening hypertensive control that required increase of antihypertensive medication(during the 3-month follow up)
- Infection requiring hospitalization(during the 3-month follow up)
- Hypokalemia(during the 3-month follow up)
- Hypercholesterolemia(during the 3-month follow up)
- Premature discontinuation from the study(during the 3-month follow up)