An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients
- Conditions
- Kidney Transplant Rejection
- Interventions
- Other: Plasma Exchange
- Registration Number
- NCT03897205
- Lead Sponsor
- Hansa Biopharma AB
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 30
- 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
- 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 polymerase chain reaction (PCR) test for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection
- Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Plasma Exchange Plasma Exchange Subjects randomized to plasma exchange (PE) treatment received 5-10 sessions of PE, as judged by the investigator. Immunoadsorption (IA) could replace PE, at the discretion of the investigator. Imlifidase Imlifidase Subjects randomized to imlifidase treatment received one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes.
- Primary Outcome Measures
Name Time Method Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment Start of treatment until 5 days following 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.
- Secondary Outcome Measures
Name Time Method Estimated Glomerular Filtration Rate (eGFR) Levels Screening until Day 180 eGFR as calculated from p-creatinine is a measure of kidney function. eGFR was assessed at all visits throughout the study.
Number of Patients With Graft Loss Within 180 Days of Treatment Screening until Day 180 Information on patients who experienced graft loss was collected throughout the study.
Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180 Day 180 Biopsies collected 180 days after treatment were analysed for signs of glomerulopathy.
DSA Functionality Determined by C1q Analysis Pre- and Post-treatment Screening until Day 6 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.
Pharmacokinetic (PK) Profile of Imlifidase: Cmax 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 Cmax = Maximum observed plasma concentration of imlifidase following dosing
PK Profile of Imlifidase: Tmax 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 Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
Reduction in DSA Levels After Treatment Screening until Day 180 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.
Urine Albumine/Creatinine Ratio Pre-dose until Day 180 The albumine/creatinine ratio in urine is a measure of kidney function.
Number of Patients With Different Types of Kidney Histopathology Throughout the Trial Screening, Day 29 and Day 180 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 rejectionNumber of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels Screening, Day 29, and Day 180 Kidney biopsies were taken at screening, Day 29, and Day 180. Changes from baseline in mRNA levels were assessed as evidence of resolved AMR.
Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions Day 1 to Day 180 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.
Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg) Pre-dose until Day 6 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.Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg 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) 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.PK Profile of Imlifidase: t1/2 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 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).
PK Profile of Imlifidase: AUC 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 Area under the imlifidase plasma concentration vs time curve (AUC)
PK Profile of Imlifidase: CL 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 Clearance (CL) of imlifidase means the volume of blood cleared of imlifidase per unit of time.
PK Profile of Imlifidase: Volume of Distribution (V) 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 Vss = volume of distribution associated with steady state VZ = volume of distribution associated with the elimination phase
Concentration of Anti-drug Antibodies (ADAs) Screening until Day 180 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.
Trial Locations
- Locations (14)
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Hôpital Pellegrin
🇫🇷Bordeaux, France
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Royal Prince Alfred Hospital
🇦🇺Sydney, Australia
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Brigham and Women Hospital
🇺🇸Boston, Massachusetts, United States
New York University Grossman School of Medicine
🇺🇸New York, New York, United States
The Royal Melbourne Hospital
🇦🇺Melbourne, Victoria, Australia
Universitätsklinik für Innere Medizin III, Klinische Abteilung für Nephrologie MUW
🇦🇹Vienna, Austria
Hôpital Saint-Louis. Service de Néphrologie et Transplantation
🇫🇷Paris, France
CHU Grenoble Alpes - Néphrologie, dialyse et transplantation
🇫🇷Grenoble, France
Hôpital Necker - Service de Néphrologie - Transplantation
🇫🇷Paris, France
Charité-Universitätsmedizin. Dept. of Nephrology and Medical Intensive Care
🇩🇪Berlin, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany