A Controlled, Open-label PA Efficacy and Safety Study in Imlifidase Desensitised Kidney Tx Patients With Positive XM Against a Deceased Donor Prior to Imlifidase Treatment, Including Non-comparative Registry and Concurrent Reference Cohorts
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 113
- 试验地点
- 43
- 主要终点
- Graft failure-free survival 1 year after transplantation following imlifidase treatment
研究概览
简要总结
An open-label post authorization efficacy and safety study evaluating graft failure-free survival at 1-year in highly sensitized end-stage renal disease (ESRD) patients with positive crossmatch (XM) against a deceased donor prior to desensitized with imlifidase and subsequent kidney transplantation. Two non-comparative reference cohorts are included to assess the impact of differences in post-transplantation management and outcome in less sensitized patients.
详细描述
After being informed about the study and potential risks, all patients giving written informed consent will undergo pre-screening to determine eligibility for study entry. All highly sensitized ESRD patients with a positive XM will be desensitized with imlifidase to convert the XM to negative and then transplanted. Following transplantation, patients will receive induction therapies (corticosteroids, rabbit anti-human thymocyte immunoglobulin (rATG)), rejection prophylaxis (high-dose intravenous immunoglobulin (IVIg), rituximab or biosimilar) and maintenance immunosuppressive therapies. The patients will be followed for 12 months.
The efficacy of imlifidase per se, i.e. rapidly cleavage of IgG to enable transplantation, is not reflected by the important clinical outcomes 1-year graft failure-free survival and kidney function. These are instead a measure of effectiveness and safety in the real-world transplantation setting. It should be noted that patient outcome is highly dependent on the post-transplantation management, as well as compliance to maintenance immunosuppressive therapy.
All patients with donor specific antibodies (DSAs) are at risk for antibody-mediated reactions (AMRs). Imlifidase removes DSA quickly and efficiently at the time of transplantation but, as with other desensitization methods, the antibodies are expected to re-occur after transplantation. The highly sensitized patients included in this trial must therefore be closely monitored for any signs of AMR. Protocol kidney biopsies will be performed at 6 months and 1 year after transplantation. For-cause biopsies, DSA and estimated glomerular filtration rate (eGFR) will be collected to assess AMR frequency.
A non-comparative concurrent reference cohort consisting of kidney transplanted patients from participating trial sites with any grade of sensitization and a negative XM towards their donor will be included in the trial to address differences in-site practice, experience, and amount of immunosuppressive therapies given that may have an impact on the overall results for the imlifidase-treated cohort. Once a highly sensitized imlifidase treated patient has been transplanted at a site, subsequent patients who are offered a compatible kidney will be offered the opportunity to be included in the trial as part of the reference cohort group and transplanted. The goal is to have at least 1 or 2 patients from each site participating in the non-comparative concurrent reference cohort. Given that the patients in this cohort will be qualitatively different from the imlifidase treated patients, formal statistical comparisons will not be appropriate. Patients included in the non-comparative concurrent reference cohort will be followed for 12 months after transplantation and treated in accordance with each clinic's normal transplantation routines.
A second, non-comparative historical reference cohort of 100 kidney transplanted patients will be randomly selected from the Collaborative Transplant Study (CTS) registry in accordance with the inclusion and exclusion criteria provided in the protocol prior to commencement of the active trial. No clinical activities will be done to this historical reference cohort. The patients of this cohort will be less sensitized compared to the imlifidase-treated cohort, have a negative XM towards their donor and have been transplanted during 2010 or later. Since patients in this cohort are expected to have both a better prognosis and a higher graft survival rate at 1 year than the imlifidase-treated patients, formal statistical comparison between the groups would be inappropriate. The year 2010 was chosen as cut-off for inclusion in the non-comparative historical reference cohort to make it likely that the patients in this group have received the same maintenance immunosuppression as is given today to most kidney transplant recipients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion criteria for ALL patients
- •Male or female patient aged 18-75 years
- •ABO-compatible deceased donor aged 10-70 years
- •Inclusion criteria for IMLIFIDASE patients
- •ESRD active on the renal transplant waiting list of a kidney allocation system at the time of screening
- •High sensitization with the highest unmet medical need unlikely to be transplanted under the available kidney allocation system including prioritisation programmes for highly sensitized patients
- •Known DSA against an available deceased donor
- •Positive crossmatch test determined by complement-dependent cytotoxicity crossmatch (CDCXM) and/or flow cytometric crossmatch (FCXM) against an available deceased donor. If physical XM tests are not practically possible due to lack of time, patients may be included on a virtual crossmatch (vXM) predictive of a positive XM test.
- •Signed Informed Consent obtained before any trial-related procedures
- •Willingness and ability to comply with the protocol
- •Inclusion criteria for patients in the NON-COMPARATIVE CONCURRENT REFERENCE COHORT
- •Active on the renal transplant waiting list at a participating trial site at the time of screening
- •An acceptable kidney transplant from a deceased donor
- •Signed Informed Consent obtained before any trial related procedures
- •Willingness and ability to comply with the protocol
- •Inclusion criteria for patients in the NON-COMPARATIVE HISTORICAL REFERENCE COHORT
- •ESRD with a kidney transplant from a deceased donor
- •Being transplanted in Europe after 01-Jan-2010 and included in the CTS registry
- •Panel reactive antibodies (PRA) ≥ 50% (CDC T- or B-cell PRA, calculated panel reactive antibodies (cPRA), or virtual panel reactive antibodies (vPRA))
- •Maintenance immunosuppression (intention to treat) with calcineurin inhibitor, mycophenolate mofetil (MMF) and corticosteroids in combination
排除标准
- •Exclusion criteria for IMLIFIDASE patients and for patients in the NON-COMPARATIVE CONCURRENT REFERENCE COHORT
- •Use of investigational agents within 5 terminal elimination half-lives prior to the transplantation
- •Malignancy within 5 years prior to transplantation
- •Positive serology for human immunodeficiency virus (HIV)
- •Clinically relevant active infection(s) as judged by the investigator
- •Contemporaneous participation in medical device studies
- •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
- •Exclusion criteria for IMLIFIDASE patients
- •Previous treatment with imlifidase
- •Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase treatment
- •Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test
- •Breast feeding or pregnancy
- •Hypersensitivity to the active substance (imlifidase) or to any of the excipients
- •Ongoing serious infections
- •Present, or history of, thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
- •Severe other condition requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent respiratory disease
- •Female of childbearing potential, not willing to use effective contraception during the 3 weeks following treatment with imlifidase. In the context of this trial, 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 such as:
- •combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; (i) oral, (ii) intravaginal, or (iii) transdermal
- •progestogen-only hormonal contraception associated with inhibition of ovulation; (i) oral, (ii) injectable, or (iii) implantable
- •intrauterine device (IUD)
- •intrauterine hormone-releasing system (IUS)
- •bilateral tubal occlusion
- •vasectomised partner
- •true abstinence: When this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]
- •Any other reason that, in the view of the investigator, precludes transplantation
- •Exclusion criteria for patients in the NON-COMPARATIVE HISTORICAL REFERENCE COHORT
- •Patients treated with mammalian target of rapamycin (mTOR) inhibitors
- •Patients treated with belatacept
研究组 & 干预措施
Non-Comparative Concurrent Reference Cohort
Patients in the non-comparative prospective concurrent reference cohort (with any grade of sensitization and negative XM) will receive medications, both pre- and post-transplant, in accordance with each clinic's routine for kidney transplanted patients.
干预措施: Normal Transplantation Routine (Other)
Non-Comparative Historical Reference Cohort
Patients in the non-comparative historical reference cohort (with less sensitization and negative XM) randomly selected from the CTS registry have been transplanted and treated in accordance with standard-of-care for kidney transplanted patients. Patients transplanted in 2010 and onwards will be selected to optimize the probability that these patients will have received about the same maintenance immunosuppressive treatment as the patients in the current trial will receive.
干预措施: Normal Transplantation Routine (Other)
Imlifidase
Imlifidase, is provided as a freeze-dried powder for concentrate for solution for infusion, 11 mg per vial. After reconstitution with sterile water for injection, the concentrate contains 10 mg/mL imlifidase. Imlifidase is administered intravenously as one infusion of 0.25 mg/kg over 15 minutes within 24 hours prior to transplantation. A second dose of 0.25 mg/kg may be given if the first imlifidase dose is considered not to have had sufficient effect. The second dose can be administered within 24 hours after the first dose.
干预措施: Imlifidase (Drug)
结局指标
主要结局
Graft failure-free survival 1 year after transplantation following imlifidase treatment
时间窗: 12 months after transplantation
Graft failure is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. Patients who die from any cause will be considered as having graft failure. If a patient is not undergoing transplantation following imlifidase treatment the patient will be censored at time zero when constructing Kaplan-Meier curves for graft failure-free survival. The 1-year graft failure-free survival rates will be extracted from Kaplan-Meier curves. Time from enrolment to the first of death or graft failure will be used as time variable.
次要结局
- Renal function up to 1 year after transplantation(Screening, pre-imlifidase, 24, 48 and 72 hours, Days 5, 6, 8, 10 and 15, at 1, 3 and 6 months and at 1 year)
- Imlifidase pharmacokinetics (t1/2)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Imlifidase pharmacokinetics (AUC)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Imlifidase pharmacokinetics (tmax)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Imlifidase pharmacokinetics (Vz)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Change in patient-reported life participation(Screening and at 1 year)
- Imlifidase pharmacokinetics (Cmax)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Proportion of patients with rejection episodes (AMRs and CMRs) during the first post-transplant year in patients with a functioning graft at the end of the first post-transplant year(From transplantation to 1 year)
- Graft survival at 1 year after transplantation(12 months after transplantation)
- HLA/DSA antibody levels up to 1 year after imlifidase treatment(Screening, pre-imlifidase, at 2, 4, 24, 48 and 72 hours, at Days 5, 6, 8, 15, at 1, 3 and 6 months, and at 1 year)
- Imlifidase pharmacodynamics(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, and 10)
- Anti-drug antibodies (ADA) levels up to 1 year after imlifidase treatment(Days 8, and 15, at 1, 3 and 6 months, and at 1 year)
- Frequency of delayed graft function (DGF)(Up to 7 days after transplantation)
- Proportion of patients with severe or serious infections within 30 days after transplantation(Up to 30 days after transplantation)
- Graft failure-free survival 1 year after transplantation in non-comparative concurrent reference cohort(12 months after transplantation)
- Patient survival at 1 year after transplantation(12 months after transplantation)
- Proportion of patients with conversion of a positive XM test to negative within 24 hours after imlifidase treatment(Pre-imlifidase, 2, 4 and 24 hours post-imlifidase.)
- Imlifidase pharmacokinetics (CL)(Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15)
- Proportion of patients with biopsy- and serology (DSA)-confirmed antibody-mediated rejections (AMRs)(Up to 12 months after transplantation)
- Proportion of patients with biopsy- and serology (DSA)-confirmed cell-mediated rejections (CMRs)(Up to 12 months after transplantation)
- Proportion of patients with infusion-related reactions within 48 hours of imlifidase infusion(Up to 48 hours after transplantation)