An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients

Study Overview
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Brief Summary
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The purpose of this study is 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 an active or chronic active antibody mediated rejection (AMR) after recently been kidney transplanted. The purpose is also to investigate and compare safety for these two treatments. 20 patients will be treated with imlifidase and 10 with PE.

Detailed Description
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Antibodies to HLA antigens have a strong correlation with allograft injury and loss. Treatment with imlifidase, PE and immunoabsorption (IA) all aim to reduce antibody levels. This study will compare the reduction in DSA levels after treatment with imlifidase and PE in patients diagnosed with active or chronic active AMR (according to Banff 2017 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 can be included regardless of serum creatinine level). Included patients will be randomized to receive either 1 dose of imlifidase (0.25 mg/kg) or 5-10 sessions of PEs (IA may replace PE at the discretion of the investigator). All patients will receive pulse methylprednisolone for 3 days, starting before the 1st treatment, followed by a tapering schedule with prednisolone/prednisone. The patients will also receive high dose IVIg 3 days after imlifidase treatment or directly after the last PE. In addition a single dose of rituximab will be given 5 days after completed IVIg infusion.

Official Title
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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

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Drug: Imlifidase
* Other: Plasma Exchange


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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 PCR test for SARS-CoV-2 virus infection Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imlifidase<br>Subjects randomized to imlifidase treatment will receive one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes. | Drug: Imlifidase<br>* Imlifidase is an IgG degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity.<br>* Other names: HMED-IdeS, IdeS, IgG endopeptidase;|
| Active Comparator: Plasma Exchange<br>Subjects randomized to plasma exchange (PE) treatment will receive 5-10 sessions of PE, as judged by the investigator. Immunoadsorption (IA) may replace PE, at the discretion of the investigator. | Other: Plasma Exchange<br>* The subject's plasma is removed and discarded and the subject receives replacement donor plasma, albumin, or a combination of albumin and saline. IA may be used instead of PE to the discretion of the investigator. IA is achieved by passing a subject's plasma over columns that bind immunoglobulins (Igs) and then the plasma is passed back to the subject.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum reduction in mean DSA level at any time point during the 5 days following the start of treatment | Maximum reduction (%) in the sum of DSAs at any time point during the 5 days following the start of treatment. Only DSAs with a pre-dose MFI ≥1000 will be included in the calculations | Start of treatment until 5 days following start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DSA levels up to 180 days after treatment | DSA levels will be assessed at all visits throughout the study. | Screening until Day 180 | 
| HLA-antibodies levels up to 180 days after treatment | HLA-antibodies levels will be assessed at all visits throughout the study. | Screening until Day 180 | 
| P-creatinine levels up to 180 days after treatment | P-creatinine is a measure of kidney function. P-creatinine will be assessed at all visits throughout the study. | Screening until Day 180 | 
| eGFR levels up to 180 days after treatment | eGFR as calculated from p-creatinine is a measure of kidney function. eGFR will be assessed at all visits throughout the study. | Screening until Day 180 | 
| Albumin/creatinine ratio in urine up to 180 days after treatment | The albumine/creatinine ratio in urine is a measure of kidney function. Urine sampling for analysis of albumine and creatinine will be done at all visits throughout the study. | Screening until 180 days after treatment | 
| Proportion of subjects with graft loss within 180 days of treatment | Information on graft loss will be collected throughout the study and proportion of subjects with graft loss will be reported. | Screening until Day 180 | 
| Proportion of subjects with signs of transplant glomerulopathy 180 days after treatment | The biopsy collected 180 days after treatment will be analysed for signs of glomerulopathy and proportion of subjects with signs of transplant glomerulopathy will be reported | Day 180 | 
| Change from baseline in histopathology at day 29 and day 180 after treatment | Kidney biopsies will be assessed according to the Banff (2017) criteria pre-dose (screening) and at day 29 and 180. | Screening, 29 days and 180 days after treatment | 
| Change from baseline in mRNA levels in kidney biopsies at day 29 and day 180 after treatment | Kidney biopsies will be taken at screening, day 29 and 180 and assessed for mRNA levels. Changes from baseline will be presented. If kidney biopsy is performed before screening, mRNA levels will be evaluated on day 29 and day 180 (no baseline will be available). | Screening, Day 29 and Day 180 | 
| Safety as evaluated by AEs | Type, frequency and intensity of treatment emergent adverse events (TEAEs) and post-treatment AEs. An AE is regarded as a TEAE if occurring up to Day 29 after start of treatment. | Start of treatment until Day 180 | 
| Number of sessions with PE | The number of PE sessions given throughout the study will be recorded in the CRF | Start of treatment until Day 180 | 
| Proportion of subjects with reduction of total serum IgG following treatment until administration of IVIg | Reduction of total serum IgG is defined as YES if the subject's minimum IgG value at any timepoint following the start of treatment and prior administration of IVIg is less than 5% of the baseline level. Proportion of subjects with a reduction of total serum IgG until administration of IVIg will be reported. | Start of treatment (Day 1) up to administration of IVIg on Day 4 | 
| Proportion of subjects with no intact IgG following treatment until administration of IVIg. | Intact IgG is analysed using SDS-PAGE/western blot. The endpoint is met if no detectable intact IgG is found at any time point following treatment until administration of IVIg. | Start of treatment (Day 1) up to administration of IVIg on Day 4 | 
| DSA functionality determined by C1q or C3d analysis pre- and post-treatment | Analysis of DSA functionality assessed as mean MFI levels will be done at all visits throughout the study. | Screening until Day 180 | 
| PK profile of imlifidase: Cmax | Cmax = Maximum observed plasma concentration of imlifidase following dosing | Start of treatment until Day 15 | 
| PK profile of imlifidase: Tmax | Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing | Start of treatment until Day 15 | 
| PK profile of imlifidase: t1/2 | t1/2 = terminal half-life of imlifidase | Start of treatment until Day 15 | 
| PK profile of imlifidase: AUC | AUC = Area under the imlifidase plasma concentration vs time curve | Start of treatment until Day 15 | 
| PK profile of imlifidase: CL | CL = Clearance of imlifidase | Start of treatment until Day 15 | 
| PK profile of imlifidase: V | V = Volume of distribution | Start of treatment until Day 15 | 
| Proportion of patients with anti-drug antibodies (ADAs) | Samples will be collected and analysed for presence anti-imlifidase IgE and anti-imlifidase IgG throughout the study. | Screening until Day 180 |