Clinical trial NCT03897205: An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Kidney Transplant Rejection
Lead sponsor: Hansa Biopharma AB
Sponsor class: INDUSTRY
First posted: 2019-04-01
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Signed Informed Consent obtained before any study-related procedures
2. Willingness and ability to comply with the protocol
3. Male and/or female donor kidney recipients age ≥18 years at the time of screening
4. Presence of DSA(s)
5. Meet the Banff 2017 criteria for active or chronic active AMR
6. 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
7. 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
8. 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:

1. Previous treatment with imlifidase
2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion
3. Lactating or pregnant females
4. Significantly abnormal general serum screening lab results judged inappropriate for inclusion in the study by the investigator
5. Intake of other investigational drugs within 5 half-lives (or similar) of the product prior to inclusion
6. Clinically relevant active infection(s) as judged by the investigator
7. 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
8. Known allergy/sensitivity to imlifidase, IVIg and/or rituximab and the respective excipients
9. Patient unable to tolerate treatment with plasmapheresis or immunoadsorption, as judged by the investigator
10. Unsuitable to participate in the study for any other reason as judged by the investigator
11. Positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection
12. Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP

Primary outcomes:
measure: Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment
timeFrame: Start of treatment until 5 days following start of treatment
Secondary outcomes:
measure: Reduction in DSA Levels After Treatment
timeFrame: Screening until Day 180
measure: Estimated Glomerular Filtration Rate (eGFR) Levels
timeFrame: Screening until Day 180
measure: Urine Albumine/Creatinine Ratio
timeFrame: Pre-dose until Day 180
measure: Number of Patients With Graft Loss Within 180 Days of Treatment
timeFrame: Screening until Day 180
measure: Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180
timeFrame: Day 180
measure: Number of Patients With Different Types of Kidney Histopathology Throughout the Trial
timeFrame: Screening, Day 29 and Day 180
measure: Number of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels
timeFrame: Screening, Day 29, and Day 180
measure: Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions
timeFrame: Day 1 to Day 180
measure: Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg)
timeFrame: Pre-dose until Day 6
measure: Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg
timeFrame: 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)
measure: DSA Functionality Determined by C1q Analysis Pre- and Post-treatment
timeFrame: Screening until Day 6
measure: Pharmacokinetic (PK) Profile of Imlifidase: Cmax
timeFrame: 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
measure: PK Profile of Imlifidase: Tmax
timeFrame: 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
measure: PK Profile of Imlifidase: t1/2
timeFrame: 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
measure: PK Profile of Imlifidase: AUC
timeFrame: 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
measure: PK Profile of Imlifidase: CL
timeFrame: 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
measure: PK Profile of Imlifidase: Volume of Distribution (V)
timeFrame: 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
measure: Concentration of Anti-drug Antibodies (ADAs)
timeFrame: Screening until Day 180
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Boston
country: United States
facility: Brigham and Women Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: New York University Grossman School of Medicine
state: New York
city: Melbourne
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
city: Vienna
country: Austria
facility: Universitätsklinik für Innere Medizin III, Klinische Abteilung für Nephrologie MUW
city: Bordeaux
country: France
facility: Hôpital Pellegrin
city: Grenoble
country: France
facility: CHU Grenoble Alpes - Néphrologie, dialyse et transplantation
city: Paris
country: France
facility: Hôpital Saint-Louis. Service de Néphrologie et Transplantation
city: Paris
country: France
facility: Hôpital Necker - Service de Néphrologie - Transplantation
city: Berlin
country: Germany
facility: Charité-Universitätsmedizin. Dept. of Nephrology and Medical Intensive Care
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
Study officials:
affiliation: Hansa Biopharma AB
name: Clinical Operations
role: STUDY_DIRECTOR
References: