The purpose of this study was 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 had an active or chronic active antibody mediated rejection (AMR) after being kidney transplanted. The purpose was also to investigate and compare safety for these two treatments.
Antibodies to human leukocyte antigens (HLAs) have a strong correlation with allograft injury and loss. Treatment with imlifidase, PE and immunoabsorption (IA) all aim to reduce antibody levels. This study compared the reduction in DSA levels after treatment with imlifidase and PE in patients diagnosed with active or chronic active AMR (according to Banff 2017 or Banff 2019 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 could be included regardless of serum creatinine level.) Eligible patients were randomized to either 1 dose of imlifidase (0.25 mg/kg) or 5-10 sessions of PEs (IA could replace PE at the discretion of the investigator). All patients received pulse methylprednisolone Day 1 to Day 3, followed by a tapering schedule with prednisolone/prednisone. Patients randomised to imlifidase received their first dose of methylprednisolone before imlifidase was administered. The patients did also receive high dose intravenous immunoglobulin (IVIg) 3 days after imlifidase treatment or directly after the last PE. In addition a single dose of rituximab was given 5 days after completed IVIg infusion.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Imlifidase is an immunoglobulin G (IgG) degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity.
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 and then the plasma is passed back to the subject.
Cedars-Sinai Medical Center
Los Angeles, California, United States
Brigham and Women Hospital
Boston, Massachusetts, United States
Mayo Clinic
Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment
Maximum reduction (%) in the sum of DSA at any time point during the 5 days following the start of treatment. Only DSA with ≥1000 mean fluorescence intensity (MFI) at pre-treatment were included in the calculations. Clarification: The higher the maximum reduction percentage the lower the remaining DSA level.
Time frame: Start of treatment until 5 days following start of treatment
Reduction in DSA Levels After Treatment
DSA levels were assessed at all visits throughout the study. The results are presented as reduction (%) from baseline. Clarification: The higher the reduction percentage the lower the remaining DSA level. Please observe that a negative reduction value represents an increase in DSA level from baseline.
Time frame: Screening until Day 180
Estimated Glomerular Filtration Rate (eGFR) Levels
eGFR as calculated from p-creatinine is a measure of kidney function. eGFR was assessed at all visits throughout the study.
Time frame: Screening until Day 180
Urine Albumine/Creatinine Ratio
The albumine/creatinine ratio in urine is a measure of kidney function.
Time frame: Pre-dose until Day 180
Number of Patients With Graft Loss Within 180 Days of Treatment
Information on patients who experienced graft loss was collected throughout the study.
Time frame: Screening until Day 180
Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180
Biopsies collected 180 days after treatment were analysed for signs of glomerulopathy.
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Rochester, Minnesota, United States
New York University Grossman School of Medicine
New York, New York, United States
The Royal Melbourne Hospital
Melbourne, Victoria, Australia
Royal Adelaide Hospital
Adelaide, Australia
Royal Prince Alfred Hospital
Sydney, Australia
Universitätsklinik für Innere Medizin III, Klinische Abteilung für Nephrologie MUW
Vienna, Austria
Hôpital Pellegrin
Bordeaux, France
CHU Grenoble Alpes - Néphrologie, dialyse et transplantation
Grenoble, France
...and 4 more locations
Time frame: Day 180
Number of Patients With Different Types of Kidney Histopathology Throughout the Trial
Kidney biopsies were assessed according to the Banff (2017) criteria at screening (baseline), Day 29, and Day 180. Abbreviations: AMR=Antibody mediated rejection, CMR=cell-mediated rejection
Time frame: Screening, Day 29 and Day 180
Number of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels
Kidney biopsies were taken at screening, Day 29, and Day 180. Changes from baseline in mRNA levels were assessed as evidence of resolved AMR.
Time frame: Screening, Day 29, and Day 180
Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions
Total number of administered PE and IA sessions to each treatment group are presented during the complete trial (Day 1 to Day 180) and for the time period: start of IVIg administration to Day 180.
Time frame: Day 1 to Day 180
Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg)
Total serum IgG levels over time following treatment until administration of IVIg. Please observe, IVIg was initiated on Day 4 (before 96 h measurement) for the imlifidase group.
Time frame: Pre-dose until Day 6
Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg
Presence of IgG, scIgG, and F(ab')2 was analysed using sodium dodecyl-sulphate polyacrylamide gel electrophoresis (SDS-PAGE)/western blot. Of note, IVIg was administered on Day 4 (before 96 h measurement) to patients treated with imlifidase. Hence no analyses beyond this timepoint were performed for this group.
Time frame: Start of treatment (Day 1) up to administration of IVIg on Day 4 (imlifidase group) and until administration of IVIg within Day 15 (PE group)
DSA Functionality Determined by C1q Analysis Pre- and Post-treatment
An MFI value above 6000 is indicative of complement fixation. Analysis of DSA functionality assessed as mean MFI levels was done before and after treatment.
Time frame: Screening until Day 6
Pharmacokinetic (PK) Profile of Imlifidase: Cmax
Cmax = Maximum observed plasma concentration of imlifidase following dosing
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: Tmax
Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: t1/2
t1/2 = terminal half-life of imlifidase (refers to the time required for plasma concentration of a drug to decrease by 50%) Different mathematical models are available to describe how drugs are adsorbed, distributed, metabolised, and eliminated from the body. The time-concentration curve of imlifidase could be fitted to the so called 2-compartment model. This model divide the body into a central and an peripheral compartment. The central compartment consist of the plasma and tissues where the distribution is fast and the peripheral consists of tissues where the distribution of the drug is slower. As a result the elimination of imlifidase consists of an initial phase with a short half life (alpha-t1/2) and an elimination phase with a longer half-life (beta-t1/2).
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: AUC
Area under the imlifidase plasma concentration vs time curve (AUC)
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: CL
Clearance (CL) of imlifidase means the volume of blood cleared of imlifidase per unit of time.
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: Volume of Distribution (V)
Vss = volume of distribution associated with steady state VZ = volume of distribution associated with the elimination phase
Time frame: Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
Concentration of Anti-drug Antibodies (ADAs)
Samples were collected and analysed for presence of anti-imlifidase IgG throughout the study. Imlifidase is an IgG-degrading enzyme of Streptococcus pyogenes. Patients who have been exposed to Streptococcus prior to participating in this trial tested positive for ADA also before exposure to imlifidase.
Time frame: Screening until Day 180