A Study to Investigate DSA Rebound in Patients Treated With Imlifidase Prior to Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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An Open Label, Phase II Study to Investigate DSA Rebound in Patients With a Positive Crossmatch, Made Transplantable With Imlifidase

Conditions
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Kidney Transplantation in Highly Sensitized Patients

Intervention / Treatment
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* Drug: Imlifidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imlifidase<br>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.) | Drug: Imlifidase<br>* Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG.<br>* Other names: IdeS, HMED-IdeS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with DSA rebound | The recurrence of DSA may cause AMR and increased risk of graft loss. Rebound of DSA is defined as: If positive flow cytometry crossmatch test (FCXM) at screening is due to low titer, non-complement binding (C1q-negative) DSAs; Immuno-dominant DSA: a post-transplant MFI value that is ≥50% the pre-imlifidase value OR Total DSAs: a post-transplant serum where ≥50% of the DSA prior to imlifidase have a MFI value ≥50% of the pre-transplant MFI value AND the sum MFI must be ≥50% of the pre-transplant value If FCXM at screening is due to high titer, complement binding (C1q-positive) DSAs; Immuno-dominant DSA: a post-transplant MFI value at 1:16 dilution that is ≥8000 MFI OR Total DSAs: a post-transplant 1:16 diluted serum where ≥50% of the DSA prior to imlifidase have an MFI value that is ≥50% of the pre-transplant MFI value AND the sum MFI must be ≥8000 | Up to 3 months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with kidney biopsy proven AMR | The standardized international Banff classification 2019 for assessment of renal allograft biopsies will be used to assess AMRs reported from the study based on for cause and protocol biopsies. | Up to 6 months after transplantation | 
| Proportion of patient with DSA rebound | See description to primary outcome measure | Up to 6 months after transplantation | 
| Proportion of patients with negative FCXM | Imlifidase is highly efficacious in converting a positive crossmatch to a negative | Up to 24 hours after imlifidase treatment | 
| Levels of DSA | Analysis of DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' DSAs. | Within 4 hours before imlifidase until Day 181 | 
| Levels complement binding (C1q) DSA | Analysis of C1q DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' C1q DSAs. | Within 4 hours before imlifidase until Day 181 | 
| Graft survival | Graft survival will be summarized by end of trial. | 6 months after transplantation | 
| Patients survival | Patient survival will be summarized by end of trial. | 6 months after transplantation | 
| Safety as measured by adverse events (AEs) | Safety is assessed as type, frequency and intensity of adverse events (AEs)/Serious adverse events (SAEs) including clinically relevant changes in clinical laboratory tests, vital signs and ECG) | Up to 6 months after transplantation | 
| Kidney function assessed by creatinine | P-creatinine is a measure of kidney function. | Up to 6 months after transplantation | 
| Kidney function assessed by estimated glomerular filtration rate (eGFR) | Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR will be calculated as described by the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is 90 mL/min/1.72m2. Kidney disease is characterised by a decreased eGFR. value. | Up to 6 months after transplantation | 
| Kidney function assessed by protein/creatinine ratio in urine | The protein/creatinine ratio in urine is a measure of kidney function. Will be measured unless patients are anuric. | Up to 6 months after transplantation | 
| Imlifidase pharmacokinetics (AUC) | AUC = Area under the imlifidase plasma concentration versus time curve | Within 4 hours before imlifidase dose until Day 15 | 
| Imlifidase pharmacokinetics (Cmax) | Cmax = Maximum observed plasma concentration of imlifidase following dosing | Within 4 hours before imlifidase dose until Day 15 | 
| Imlifidase pharmacokinetics (tmax) | tmax = Time point for maximum observed plasma concentration of imlifidase following dosing | Within 4 hours before imlifidase dose until Day 15 | 
| Imlifidase pharmacokinetics (t1/2) | t1/2 = Terminal half-life of imlifidase | Within 4 hours before imlifidase dose until Day 15 | 
| Imlifidase pharmacokinetics (CL) | CL = Clearance of imlifidase | Within 4 hours before imlifidase dose until Day 15 | 
| Imlifidase pharmacokinetics (Vz) | Vz = Apparent volume of distribution during terminal phase | Within 4 hours before imlifidase dose until Day 15 | 
| Pharmacodynamics | Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done. | Within 4 hours before imlifidase dose until Day 10 | 
| Anti-drug antibodies (ADA) levels | Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis. | Up to 6 months after imlifidase | 
| Change in patient-reported life participation, as measured PROMIS-SF-8a | The PROMIS Social Health domain Ability to participate in social roles & activities PROMIS-SF-8 will be used as a measure of the patients' health related quality of life. | At screening and Day 181 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Highly sensitized, Kidney transplantation, Renal transplantation