A Randomized, Open-Label, Multi-Centre, Active Control, Efficacy and Safety Study of Imlifidase in Eliminating Donor Specific Anti-HLA Antibodies in the Treatment of Active Antibody-Mediated Rejection in Kidney Transplant Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 14
- 主要终点
- Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment
研究概览
简要总结
The purpose of this study was to investigate how efficiently the study medication imlifidase reduces the amount of donor specific antibodies (DSA) in comparison with plasma exchange (PE) therapy, in patients who have had an active or chronic active antibody mediated rejection (AMR) after being kidney transplanted. The purpose was also to investigate and compare safety for these two treatments.
详细描述
Antibodies to human leukocyte antigens (HLAs) have a strong correlation with allograft injury and loss. Treatment with imlifidase, PE and immunoabsorption (IA) all aim to reduce antibody levels.
This study compared the reduction in DSA levels after treatment with imlifidase and PE in patients diagnosed with active or chronic active AMR (according to Banff 2017 or Banff 2019 criteria) having at least a 25% rise in serum creatinine compared with last measurement prior to the AMR. (Patients with delayed graft function and AMR within 10 days after kidney transplantation could be included regardless of serum creatinine level.) Eligible patients were randomized to either 1 dose of imlifidase (0.25 mg/kg) or 5-10 sessions of PEs (IA could replace PE at the discretion of the investigator).
All patients received pulse methylprednisolone Day 1 to Day 3, followed by a tapering schedule with prednisolone/prednisone. Patients randomised to imlifidase received their first dose of methylprednisolone before imlifidase was administered. The patients did also receive high dose intravenous immunoglobulin (IVIg) 3 days after imlifidase treatment or directly after the last PE. In addition a single dose of rituximab was given 5 days after completed IVIg infusion.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed Informed Consent obtained before any study-related procedures
- •Willingness and ability to comply with the protocol
- •Male and/or female donor kidney recipients age ≥18 years at the time of screening
- •Presence of DSA(s)
- •Meet the Banff 2017 criteria for active or chronic active AMR
- •At least 25% rise in serum creatinine compared to last individual value taken prior to the AMR. Patients with delayed graft function and AMR within 10 days after transplant (confirmed by kidney biopsy) can be included regardless of serum creatinine level
- •Women of child-bearing potential willing or able to use at least one highly effective contraceptive method throughout the study. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly
- •Men willing to use double-barrier contraception from the first day of treatment until at least 2 months after the dose of imlifidase, if not abstinent
排除标准
- •Previous treatment with imlifidase
- •Previous high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion
- •Lactating or pregnant females
- •Significantly abnormal general serum screening lab results judged inappropriate for inclusion in the study by the investigator
- •Intake of other investigational drugs within 5 half-lives (or similar) of the product prior to inclusion
- •Clinically relevant active infection(s) as judged by the investigator
- •Any condition that in the opinion of the investigator could increase the subject's risk by participating in the study such as severe immune deficiency and severe cardiac insufficiency [New York Heart Association (NYHA) Class IV] or severe uncontrolled heart disease
- •Known allergy/sensitivity to imlifidase, IVIg and/or rituximab and the respective excipients
- •Patient unable to tolerate treatment with plasmapheresis or immunoadsorption, as judged by the investigator
- •Unsuitable to participate in the study for any other reason as judged by the investigator
- •Positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection
- •Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
研究组 & 干预措施
Imlifidase
Subjects randomized to imlifidase treatment received one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes.
干预措施: Imlifidase (Drug)
Plasma Exchange
Subjects randomized to plasma exchange (PE) treatment received 5-10 sessions of PE, as judged by the investigator. Immunoadsorption (IA) could replace PE, at the discretion of the investigator.
干预措施: Plasma Exchange (Other)
结局指标
主要结局
Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment
时间窗: Start of treatment until 5 days following start of treatment
Maximum reduction (%) in the sum of DSA at any time point during the 5 days following the start of treatment. Only DSA with ≥1000 mean fluorescence intensity (MFI) at pre-treatment were included in the calculations. Clarification: The higher the maximum reduction percentage the lower the remaining DSA level.
次要结局
- Estimated Glomerular Filtration Rate (eGFR) Levels(Screening until Day 180)
- Number of Patients With Graft Loss Within 180 Days of Treatment(Screening until Day 180)
- Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180(Day 180)
- DSA Functionality Determined by C1q Analysis Pre- and Post-treatment(Screening until Day 6)
- Pharmacokinetic (PK) Profile of Imlifidase: Cmax(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- PK Profile of Imlifidase: Tmax(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- Reduction in DSA Levels After Treatment(Screening until Day 180)
- Urine Albumine/Creatinine Ratio(Pre-dose until Day 180)
- Number of Patients With Different Types of Kidney Histopathology Throughout the Trial(Screening, Day 29 and Day 180)
- Number of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels(Screening, Day 29, and Day 180)
- Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions(Day 1 to Day 180)
- Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg)(Pre-dose until Day 6)
- Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg(Start of treatment (Day 1) up to administration of IVIg on Day 4 (imlifidase group) and until administration of IVIg within Day 15 (PE group))
- PK Profile of Imlifidase: t1/2(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- PK Profile of Imlifidase: AUC(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- PK Profile of Imlifidase: CL(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- PK Profile of Imlifidase: Volume of Distribution (V)(Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15)
- Concentration of Anti-drug Antibodies (ADAs)(Screening until Day 180)