An Open Label, Phase II Study to Investigate DSA Rebound in Patients With a Positive Crossmatch, Made Transplantable With Imlifidase
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Proportion of Patients With DSA Rebound
研究概览
简要总结
The purpose of this study is to assess whether imlifidase in combination with bortezomib, belatacept, rituximab and IVIg can suppress donor specific antibodies (DSA) and the occurrence of antibody-mediated rejection (AMR) in highly sensitized patients with chronic kidney disease with a positive crossmatch towards their living donor during a period of 3 months from transplantation.
详细描述
Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG. Clinical studies with imlifidase have demonstrated that the treatment enables transplantation in patients otherwise highly unlikely to be transplanted, by converting a positive crossmatch to a negative.
However, as with other desensitization methods, DSA tend to reappear within weeks after treatment and transplantation, which may cause AMR and increased risk of graft loss. In this study, treatment with imlifidase in combination with approved drugs that prevent or suppress DSA rebound by targeting antibody-producing plasma-cells and their B-cell precursors is suggested. These drugs include (i) bortezomib, a proteasome inhibitor which has activity against mature plasma cells, the source of DSA, (ii) belatacept, a fusion protein which is crucial in blocking T-cell co-stimulation and which is effective in reducing de novo DSA generation in humans, (iii) rituximab, an anti-CD20 monoclonal antibody that targets B-cells and which is an immunomodulatory agent, and (iv) intravenous immunoglobulin (IVIg) which is commonly used in desensitization regimens and for the treatment of AMR.
After being informed about the study and potential risks, all patients giving written informed consent will undergo a 2-week screening period to determine eligibility for study entry. Patients who meet the eligibility requirements will then start treatment with belatacept and bortezomib about 3 weeks prior to the imlifidase infusion and transplantation. Rituximab will be initiated 8 days after transplantation and IVIg 10 days after transplantation. Induction and maintenance immunosuppression will also be administered. The patients will be hospitalized for approximately 2 weeks following transplantation and after that 9 follow-up visits to the clinic will take place up to 6 months after transplantation.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed Informed Consent obtained before any trial-related procedures
- •Male or female age 18 to 70 years at the time of screening
- •Highly sensitized patients registered on the UNOS waiting list for kidney transplantation, with either of the following:
- •cPRA ≥ 99.9%
- •cPRA ≥ 98% and have been in kidney paired donation or kidney paired exchange programs for at least 1 year
- •A positive crossmatch towards a living donor
- •Willingness and ability to comply with the protocol
排除标准
- •Previous treatment with imlifidase
- •Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase treatment
- •Breast-feeding or pregnancy
- •Women of child-bearing potential not willing or able to practice FDA-approved forms of contraception. Two medically acceptable methods of highly effective contraception must be used for the duration of the study (e.g. oral, transdermal, intravaginal, injectable or implantable contraceptive; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; bilateral tubal occlusion; or double-barrier method). For a woman to be considered postmenopausal this ascertainment must be made according to medical records and clinical history and may be aided by measurement of elevated postmenopausal serum gonadotropin levels (FSH).
- •ABO blood group incompatible transplantations (A2 and A2B kidneys will not be accepted for B recipients)
- •Positive serology for HIV
- •Clinical signs of HBV, HCV, CMV, or EBV infection
- •EBV seronegative or with unknown EBV serostatus
- •Positive SARS-CoV-2 tests at any time point from screening to transplantation
- •Active tuberculosis
- •Ongoing serious infections as judged by the investigator
- •Severe other conditions requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent respiratory disease
- •A history of a proven hypercoagulable condition
- •Present, or history of, thrombotic thrombocytopenic purpura (TTP) or known familial history of TTP
- •Intake of investigational drugs (other than imlifidase) within 5 half-lives
- •Contemporaneous participation in a medical device study
- •Known allergy/sensitivity (except local reactions) to imlifidase or to any drug (or the excipients) specified in the protocol
- •Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities
- •Inability by the judgement of the investigator to participate in the trial for any other reason
研究组 & 干预措施
Imlifidase
Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.)
干预措施: Imlifidase (Drug)
结局指标
主要结局
Proportion of Patients With DSA Rebound
时间窗: Up to 3 months after transplantation
The recurrence of DSA may cause AMR and increased risk of graft loss. Due to the early termination of the trial the primary endpoint was assessed as the incidence of DSA rebound of either immunodominant or total DSA to a mean fluorescence intensity (MFI) level that was ≥50% of the pre-imlifidase value up to 3 months after transplantation (trial day 91).
次要结局
- Proportion of Patients With Kidney Biopsy Proven AMR(Up to 6 months after transplantation)
- Proportion of Patient With DSA Rebound(Up to 6 months after transplantation)
- Proportion of Patients With Negative FCXM(Up to 24 hours after imlifidase treatment)
- Levels of DSA(Within 4 hours before imlifidase until Day 181)
- Levels of Complement Binding (C1q) DSA(Within 4 hours before imlifidase until Day 181)
- Number of Participants With Graft Survival(6 months after transplantation)
- Patients Survival(6 months after transplantation)
- Kidney Function Assessed by Estimated Glomerular Filtration Rate (eGFR)(Up to 6 months after transplantation)
- Number of Participants With Adverse Events (AEs)(Up to 6 months after transplantation)
- Kidney Function Assessed by Creatinine(Up to 6 months after transplantation)
- Kidney Function Assessed by Protein/Creatinine Ratio in Urine(Up to 6 months after transplantation)
- Imlifidase Pharmacokinetics (AUC)(Within 4 hours before imlifidase dose until Day 15)
- Imlifidase Pharmacokinetics (Cmax)(Within 4 hours before imlifidase dose until Day 15)
- Imlifidase Pharmacokinetics (Tmax)(Within 4 hours before imlifidase dose until Day 15)
- Imlifidase Pharmacokinetics (t1/2)(Within 4 hours before imlifidase dose until Day 15)
- Imlifidase Pharmacokinetics (CL)(Within 4 hours before imlifidase dose until Day 15)
- Imlifidase Pharmacokinetics (Vz)(Within 4 hours before imlifidase dose until Day 15)
- Pharmacodynamics(Within 4 hours before imlifidase dose until Day 10)
- Anti-drug Antibodies (ADA) Levels(Up to 6 months after imlifidase)
- Change in Patient-reported Life Participation, as Measured PROMIS-SF-8a(At screening and Day 181)