Assessing Residual Inflammation and Macrophage Presence in Lupus Nephritis After 3 Months of Intensified Treatment With Prednisolone, Mycofenolate Mofetil and Voclosporin as Compared to Mycofenolate Mofetil and Prednisolone, an Open Label Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 55
- 试验地点
- 1
- 主要终点
- Determining single cell RNA sequencing differences within the full macrophage spectrum between arm 1 vs arm 2
研究概览
简要总结
The goal of this clinical trial is to learn how different treatments affect immune cells in the kidney in people with active lupus nephritis (LN), a kidney manifestation of systemic lupus erythematosus (SLE). It will also investigate whether early changes in kidney tissue can predict long-term treatment response and whether blood or urine biomarkers can be used to monitor disease activity without the need for repeat kidney biopsies.
The main questions it aims to answer are:
- Does adding voclosporin to standard treatment with mycophenolate mofetil (MMF) and prednisolone result in greater early improvement of kidney inflammation compared with MMF and prednisolone alone?
- Are specific macrophage and monocyte populations associated with treatment response and long-term kidney outcomes?
- Can blood- or urine-based biomarkers be identified that reflect kidney inflammation and treatment response?
Researchers will compare MMF, prednisolone, and voclosporin (triple therapy) with MMF and prednisolone alone (dual therapy) to determine whether intensified treatment leads to faster and more complete immunological and histological remission.
Participants with newly diagnosed or relapsing proliferative lupus nephritis will:
- Be randomly assigned to receive either triple therapy (MMF, prednisolone, and voclosporin) or dual therapy (MMF and prednisolone).
- Undergo a kidney biopsy before treatment starts and a repeat kidney biopsy after 3 months of treatment.
- Provide blood and urine samples during follow-up for immune cell analyses and biomarker studies.
- Complete patient-reported outcomes questionnaires
- Attend regular study visits and clinical assessments for up to 2 years.
In addition, participants with SLE without lupus nephritis and healthy volunteers will provide blood samples to allow comparison of circulating immune cell populations between groups.
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
- 16 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Lupus nephritis patients
- •Inclusion Criteria:
- •Patients with de novo or flaring SLE according to the EULAR/ACR criteria and a suspicion of class III or IV LN with a clinical indication to perform a kidney biopsy
- •Age 16-70 years
- •eGFR as measured by cystatin C >20 mL/min
排除标准
- •LN class I, II or pure class V upon kidney biopsy
- •eGFR as measured by cystatin C <20 mL/min
- •Histological chronicity score (NIH) of 8 or higher in the kidney biopsy
- •Active infection of any kind as evidenced by cultures (blood, urine or otherwise)
- •History of hepatitis B, hepatitis C, tuberculosis and/or HIV
- •Treatment with any of the following agents within one month before screening:
- •tacrolimus, belimumab, anifrolumab - Treatment with any of the following agents within 6 months before screening: rituximab, daratumumab, eculizumab
- •Prolongation of QT-interval (QTc >470ms) and/or bradycardia (resting heart rate <50bpm) measured on two separate occasions
- •Hyperkalaemia (serum potassium >6.0 mmol/L)
- •Hypertension (blood pressure > 165/105 mmHg, with symptoms of hyperten sion)*
- •Co-administration of voclosporin with strong CYP3A4 inhibitors (e.g., ke toconazole, itraconazole, clarithromycin)
- •Pregnancy
- •A single elevated blood pressure measurement will not lead to immediate exclusion from the trial. Antihypertensive therapy may be initiated as appropriate. Dose adjustments of voclosporin should be made in accordance with Section 11.3.2 of the protocol
- •SLE patients without LN (disease control group) Inclusion criteria
- •Diagnosis of SLE according to EULAR/ACR guidelines
- •Age 16-70
- •Exclusion criteria
- •Suspicion of LN
- •Signs of active infection
- •Healthy subjects (control group) Inclusion criteria
- •Blank medical history
- •Age 16-70
- •A majority (75%) of female healthy subjects will be sought
- •Exclusion criteria
- •- Signs of active infection
研究组 & 干预措施
Dual Therapy (MMF + Prednisolone)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, and mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily).
干预措施: Mycophenolate Mofetil (MMF) Treatment (Drug)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: Kidney Biopsy (Procedure)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: Voclosporin (LUPKYNIS) (Drug)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: Blood, feces and urine sample collection (Diagnostic Test)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: LupusPRO questionnaire (Other)
Dual Therapy (MMF + Prednisolone)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, and mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily).
干预措施: Blood, feces and urine sample collection (Diagnostic Test)
Dual Therapy (MMF + Prednisolone)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, and mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily).
干预措施: LupusPRO questionnaire (Other)
Dual Therapy (MMF + Prednisolone)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, and mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily).
干预措施: Kidney Biopsy (Procedure)
SLE without LN control
From the SLE without LN patients (disease control), blood and urine samples are collected at two timepoints, with an interval of (min) 3 and (max) 6 months between collection. Participants in this arm are not randomized and do not undergo treatment or kidney biopsy.
Healthy control
Healthy participants (healthy control) blood and urine samples are collected at two timepoints, with an interval of (min) 3 and (max) 6 months between collection. Participants in this arm are not randomized and do not undergo treatment or kidney biopsy.
Dual Therapy (MMF + Prednisolone)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, and mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily).
干预措施: Prednisolone (Drug)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: Mycophenolate Mofetil (MMF) Treatment (Drug)
Triple Therapy (MMF + Prednisolone + Voclosporin)
Participants receive induction corticosteroid therapy consisting of intravenous methylprednisolone 500 mg daily for 3 days, followed by oral prednisolone 1 mg/kg/day with tapering to ≤5 mg/day within 3 months, mycophenolate mofetil (MMF) 1000 mg twice daily (or 500 mg four times daily), and voclosporin 23.7 mg twice daily.
干预措施: Prednisolone (Drug)
结局指标
主要结局
Determining single cell RNA sequencing differences within the full macrophage spectrum between arm 1 vs arm 2
时间窗: From enrollment to the repeat kidney biopsy at 3 months after starting treatment
The macrophage spectrum will be compared between baseline kidney biopsy and kidney biopsy at 3 months treatment. Differences in celltype proportions, gene expression and spatial organization will be assessed using spatial single cell RNA sequencing techniques.
次要结局
- Analyze rapid clinical remission of intensified treatment by proteinuria levels for relation to tissue changes(From enrollment to the end of follow-up at 24 months)
- Assess differences in macrophage subtypes within kidney tissue(From enrollment to the repeat kidney biopsy at 3 months after starting treatment)
- Assess histological response of both treatment arms(From enrollment to the repeat kidney biopsy at 3 months after starting treatment)
- To assess phenotype of circulating monocytes in LN patients compared to SLE patients without clinical kidney involvement and healthy participants(From enrollment to the end of follow-up at 24 months)
- To identify potential non-invasive urinary biomarkers(From enrollment to the end of follow-up at 24 months)
- Confirm scRNA-seq identified macrophage markers immunohistochemically, identify spatial distribution (glomerular vs interstitial) and assess their predictive and prognostic use.(From enrollment to the end of follow-up at 24 months)
研究者
Marc L. Hilhorst
MD, PhD
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)