Safety, Tolerability and Efficacy of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection After Kidney Transplantation - a Pilot Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Number of adverse events and severe adverse events (AE's, SAE's)
研究概览
简要总结
This bi-center study (Medical University of Vienna & Charité Berlin) is an investigator-driven pilot trial designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy (preliminary assessment) of humanized anti-IL-6 monoclonal antibody clazakizumab in kidney transplant recipients with late antibody-mediated rejection (ABMR). The study is designed as a phase 2 trial and has two subsequent sub-parts, a randomized placebo-controlled trial (part A) of 12 weeks, where recipients are allocated to receive either anti-IL-6 antibody clazakizumab (n=10) or placebo (n=10), followed by an open-label prospective study, where all 20 study patients will receive clazakizumab for a period of 40 weeks. Study protocol biopsies will be performed at the end of part A and part B.
详细描述
Part A:
Patients positive for anti-HLA donor-specific antibodies (DSA) and with biopsy-proven late ABMR (Acute/active or chronic/active phenotype according to the Banff 2015 classification) will be identified and recruited at the kidney transplantation outpatient services of the two center sites. Participants will be randomized to receive either clazakizumab or placebo subcutaneously (1:1 randomization stratified for ABMR type) for a period of 12 weeks (administration of clazakizumab/placebo at day 0, and after 4 and 8 weeks). After 12 weeks, patients will be subjected to a first follow-up biopsy. Primary goals of this part of the trial are to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a short course of treatment. Moreover, part A will allow for a first preliminary assessment of the impact of clazakizumab on ABMR-associated inflammation detected in peripheral blood and in the rejecting organ allograft, on the pharmacokinetics of pantoprazole as a probe drug to investigate influence of IL-6 blockade on cytochrome P450 (CYP) dependent drug metabolism (potential effects on the half-life of CYP-metabolized drugs such as pantoprazole, and on the short-term course of DSA mean fluorescence intensity (MFI) and kidney allograft function (eGFR, urinary protein excretion). The randomization sequence will be unblinded for a first data analysis after the last patient has completed the 12-week follow-up period.
Part B:
After completion of part A after 12 weeks, all study patients will enter part B, an open-label part of the study. All 20 subjects will receive subcutaneous clazakizumab in 4-weekly intervals until the end-of-study (EOS) visit after 52 weeks and will then be subjected to a second protocol biopsy. Major goals of part B are to evaluate the safety and tolerability of a prolonged period of treatment with clazakizumab and the long-term impact of this antibody on the evolution of ABMR, rejection-associated biomarkers and kidney allograft function and survival over a period of 12 months.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntary written informed consent
- •Age >18 years
- •Functioning living or deceased donor allograft after ≥365 days post-transplantation
- •eGFR >30 ml/min/1.73 m2
- •Detection of HLA class I and/or II antigen-specific antibodies (preformed and/or de novo DSA).
- •Acute/active or chronic/active ABMR (±C4d in PTC) according to Banff 2013/2015
- •Molecular ABMR score (ABMRpm) ≥0.2
排除标准
- •Patients actively participating in another clinical trial
- •Age ≤18 years
- •Female subject is pregnant or lactating
- •Index biopsy results:
- •T-cell-mediated rejection classified Banff grade ≥I
- •De novo or recurrent severe thrombotic microangiopathy
- •Polyoma virus nephropathy
- •De novo or recurrent glomerulonephritis
- •Acute rejection treatment <3 month before screening
- •Acute deterioration of graft function (eGFR decline within 1-3 months >25%)
- •Nephrotic range proteinuria >3500 mg/g protein/creatinine ratio
- •Active viral, bacterial or fungal infection precluding intensified immunosuppression
- •Active malignant disease precluding intensified immunosuppressive therapy
- •Abnormal liver function tests (ALT, AST, bilirubin > 1.5 x upper limit of normal)
- •Other significant liver disease
- •Latent or active tuberculosis (positive QuantiFERON-TB-Gold test, Chest X-ray)
- •Administration of a live vaccine within 6 weeks of screening
- •Neutropenia (<1 G/L) or thrombocytopenia (<100 G/L)
- •History of gastrointestinal perforation, diverticulitis, or inflammatory bowel disease
- •Allergy against proton pump inhibitors
- •History of alcohol or illicit substance abuse
- •Serious medical or psychiatric illness likely to interfere with participation in the study
研究组 & 干预措施
Clazakizumab / Clazakizumab
Monthly subcutaneous injections of 25mg clazakizumab for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
干预措施: Clazakizumab / Clazakizumab (Drug)
Placebo / Clazakizumab
Monthly subcutaneous injections of placebo (saline) for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
干预措施: Placebo / Clazakizumab (Drug)
结局指标
主要结局
Number of adverse events and severe adverse events (AE's, SAE's)
时间窗: 12 months
Serious and Non-Serious adverse events probably or possibly attributable to clazakizumab
次要结局
- Anti-clazakizumab antibodies in serum(At 0, 12 and 52 weeks)
- Clazakizumab serum concentration(At 0, 12 and 52 weeks)
- Allograft function - eGFR(At day 0, week 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 51 and 52)
- Allograft function - protein excretion in spot urine(At day 0, week 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 51 and 52)
- Anti-HLA antibody levels - antibody strength(At 0, 12 and 52 weeks)
- Anti-HLA antibody levels - broadness of antibody reactivity(At 0, 12 and 52 weeks)
- IgG subclass 3 (IgG3)(At 0, 12 and 52 weeks)
- Total IgM concentration(At 0, 12 and 52 weeks)
- IgG subclass 4 (IgG4)(At 0, 12 and 52 weeks)
- Patient survival(12 months)
- Pantoprazole serum concentration(At 0, 12 and 52 weeks)
- Protocol biopsy results - microcirculation inflammation(At week 11 and at week 52)
- Protocol biopsy results - chronic damage(At week 11 and at week 52)
- Total IgG concentration(At 0, 12 and 52 weeks)
- Protocol biopsy results - molecular signs of ABMR(At week 11 and at week 52)
- Protocol biopsy results - ABMR phenotype(At week 11 and at week 52)
- Anti-HLA antibody levels - number of DSA(At 0, 12 and 52 weeks)
- IgG subclass 1 (IgG1)(At 0, 12 and 52 weeks)
- Effect on leukocyte subsets in peripheral blood(At 0, 12 and 52 weeks)
- Total IgA concentration(At 0, 12 and 52 weeks)
- IgG subclass 2 (IgG2)(At 0, 12 and 52 weeks)
- Effect on IL-6R gene expression in peripheral blood cells(At 0, 12 and 52 weeks)
- Graft survival(12 months)
- Cytokine patterns and endothelial activation/injury markers in serum(At 0, 12 and 52 weeks)
- Effect on IL-6 gene expression in peripheral blood cells(At 0, 12 and 52 weeks)
- Occurrence of biopsy-proven acute rejection necessitating rejection treatment(At week 52)
研究者
Farsad Eskandary
Principal Investigator
Medical University of Vienna