Kidney Transplantation in Highly Sensitized Patients
Conditions
Keywords
Desensitization, Highly sensitized, Positive crossmatch, Unlikely to be transplanted, Renal transplantation, Kidney transplantation, Deceased donor, End-Stage Renal Disease, ESRD
Brief summary
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.
Detailed description
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.
Interventions
DRUGImlifidase
Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly selective towards IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG.
OTHERNormal Transplantation Routine
Transplantation and pre- and post-transplantation therapies in accordance with the clinic's normal transplantation routine.
Sponsors
Hansa Biopharma AB
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label, non-randomised trial in highly sensitized adult kidney transplant patients with positive XM against an available deceased donor. The rational for a non-randomised trial is that no other effective or approved desensitization protocol exists in deceased-donor kidney transplantation that would provide a suitable control. A non-comparative concurrent reference cohort from participating sites will be included to address differences in-site practice and experience. A non-comparative historical reference cohort from the CTS registry will be included to address the outcome in a less sensitized patient group.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Inclusion criteria for ALL patients 1. Male or female patient aged 18-75 years 2. ABO-compatible deceased donor aged 10-70 years Inclusion criteria for IMLIFIDASE patients 1. ESRD active on the renal transplant waiting list of a kidney allocation system at the time of screening 2. 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 3. Known DSA against an available deceased donor 4. 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. 5. Signed Informed Consent obtained before any trial-related procedures 6. Willingness and ability to comply with the protocol Inclusion criteria for patients in the NON-COMPARATIVE CONCURRENT REFERENCE COHORT 1. Active on the renal transplant waiting list at a participating trial site at the time of screening 2. An acceptable kidney transplant from a deceased donor 3. Signed Informed Consent obtained before any trial related procedures 4. Willingness and ability to comply with the protocol Inclusion criteria for patients in the NON-COMPARATIVE HISTORICAL REFERENCE COHORT 1. ESRD with a kidney transplant from a deceased donor 2. Being transplanted in Europe after 01-Jan-2010 and included in the CTS registry 3. Panel reactive antibodies (PRA) ≥ 50% (CDC T- or B-cell PRA, calculated panel reactive antibodies (cPRA), or virtual panel reactive antibodies (vPRA)) 4. Maintenance immunosuppression (intention to treat) with calcineurin inhibitor, mycophenolate mofetil (MMF) and corticosteroids in combination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft failure-free survival 1 year after transplantation following imlifidase treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Renal function will be assessed at several timepoints for the imlifidase-treated cohort, the non-comparative concurrent reference cohort and the non-comparative historical reference cohort. Of note, less frequent sampling is done to the non-comparative concurrent reference cohort as compared with the imlifidase treatment group. For the historical reference cohort kidney function will be measured by serum/plasma creatinine category at 3 and 6 months and 1 year (130 µmol/L, 130-259 µmol/L, 260-400 µmol/L and \>400 µmol/L). eGFR will be available only in selected patients in the historical control cohort. eGFR is a measure of kidney function. The serum/plasma creatinine levels will be analysed and eGFR will be calculated according to the modification of diet in renal disease (MDRD) equation. Reduced kidney function is characterised by a decreased eGFR value. eGFR will be set to 0 for patients treated with imlifidase who are not successfully transplanted. |
| Patient survival at 1 year after transplantation | 12 months after transplantation | Patient survival will be assessed for the imlifidase-treated cohort, the non-comparative concurrent reference cohort and the non-comparative historical reference cohort. The 1-year patient survival rates will be extracted from Kaplan-Meier curves. |
| Graft survival at 1 year after transplantation | 12 months after transplantation | Graft survival will be assessed for the imlifidase-treated cohort, the non-comparative concurrent reference cohort and the non-comparative historical reference cohort. Graft survival will be presented with Kaplan-Meier curves. Graft failure is defined as permanent return to dialysis for at least 6 weeks, re-transplantation, or nephrectomy. Patients who die will be censored at time of death. |
| 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. | This outcome is applicable for the imlifidase-treated cohort only. XM testing will be performed using CDCXM and FCXM (B- and T-cells). If any of the B- or T-cells or both are positive, the patient is categorised as having a positive XM test. |
| 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 | This outcome will be assessed for the imlifidase-treated cohort only. HLA antibodies will be analysed throughout the study using an IgG single antigen solid-phase immunoassay for class I and class II (SAB-HLA). Donor specific antibodies (DSAs) are identified by using the human leukocyte antigen (HLA) profile data from the donor and the recipient to identify HLA-mismatches. Antibodies directed against donor HLA with levels \>1000 mean fluorescence intensity (MFI) prior to imlifidase infusion are considered pre-transplant DSAs. The MFIs will be summarized for all DSAs with an MFI of ≥1000 at any time during the trial. |
| Imlifidase pharmacokinetics (AUC) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | AUC = Area under the imlifidase plasma concentration versus time curve Sampling for pharmacokinetic (PK) analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| Imlifidase pharmacokinetics (Cmax) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | Cmax = Maximum observed plasma concentration of imlifidase following dosing. Sampling for PK analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| Imlifidase pharmacokinetics (tmax) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | tmax = Time point for maximum observed plasma concentration of imlifidase following dosing. Sampling for PK analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| Imlifidase pharmacokinetics (t1/2) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | t1/2 = Terminal half-life of imlifidase Sampling for PK analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| Imlifidase pharmacokinetics (CL) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | CL = Clearance of imlifidase. Sampling for PK analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| Graft failure-free survival 1 year after transplantation in non-comparative concurrent reference cohort | 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. 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. |
| Imlifidase pharmacodynamics | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, and 10 | IgG concentration in patient serum will be measured. Composition of IgG fragments will be analysed and scored. Sampling for pharmacodynamic (PD) analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
| 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 | This outcome is applicable for the imlifidase-treated cohort only. Determination of anti-imlifidase IgG (ADA) concentration in serum will be performed centrally using a customised ImmunoCAP. |
| Frequency of delayed graft function (DGF) | Up to 7 days after transplantation | Delayed graft function (DGF) will be assessed for the imlifidase-treated cohort and the non-comparative concurrent reference cohort. DGF is defined as need for dialysis within 7 days of transplantation. |
| Proportion of patients with biopsy- and serology (DSA)-confirmed antibody-mediated rejections (AMRs) | Up to 12 months after transplantation | Frequency of AMRs will be assessed for the imlifidase-treated cohort and the non-comparative concurrent reference cohort. This includes protocol biopsies at 6 months and 1 year after transplantation in the imlifidase treatment group. For-cause biopsies will be obtained to confirm diagnosis for suspected AMRs in both treatment arms. All kidney biopsies (protocol and for-cause) in both cohorts will be evaluated according to Banff criteria version 2017 or later. DSA and eGFR will be analysed centrally for the imlifidase group and locally for the concurrent reference cohort. |
| Proportion of patients with biopsy- and serology (DSA)-confirmed cell-mediated rejections (CMRs) | Up to 12 months after transplantation | Frequency of CMRs will be assessed for the imlifidase-treated cohort and the non-comparative concurrent reference cohort. This includes protocol biopsies at 6 months and 1 year after transplantation in the imlifidase treatment group. For-cause biopsies will be obtained to confirm diagnosis for suspected AMRs in both treatment arms. All kidney biopsies (protocol and for-cause) in both cohorts will be evaluated according to Banff criteria version 2017 or later. DSA and eGFR will be analysed centrally for the imlifidase group and locally for the concurrent reference cohort. |
| Proportion of patients with infusion-related reactions within 48 hours of imlifidase infusion | Up to 48 hours after transplantation | This outcome is applicable for the imlifidase-treated cohort only. Infusion-related reactions that occurs within 48 hours of imlifidase treatment are considered adverse events of special interest (AESI). |
| Proportion of patients with severe or serious infections within 30 days after transplantation | Up to 30 days after transplantation | This outcome will be assessed for the imlifidase-treated cohort and the non-comparative concurrent reference cohort. Severe or serious infections within 30 days after transplantation are considered AESI for both these cohorts. |
| Change in patient-reported life participation | Screening and at 1 year | This outcome will be assessed for the imlifidase-treated cohort and the non-comparative concurrent reference cohort. The Patient-Reported Outcomes Measurement Information System (PROMIS) Social Health domain Ability to participate in social roles & activities Short Form 8a will be used as a measure of the patients' health related quality of life. The questionnaire includes 8 questions about a persons ability to participate in different social activities and there are 5 different answers to choose from for each question: Never/Rarely/Sometimes/Usually/Always |
| 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 | This outcome will be assessed for the non-comparative historical reference cohort only. Data for AMR/CMR rejection episodes during the first post-transplant year will be collected from the CTS registry. |
| Imlifidase pharmacokinetics (Vz) | Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15 | CL = Clearance of imlifidase. Sampling for PK analyses will be performed for a subgroup of about 20 imlifidase treated patients at a selected number of sites. |
Countries
Austria, Belgium, Czechia, France, Germany, Italy, Netherlands, Slovenia, Spain, Sweden, United Kingdom
Outcome results
None listed