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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03897205




Registration number
NCT03897205
Ethics application status
Date submitted
27/03/2019
Date registered
1/04/2019
Date last updated
28/02/2024

Titles & IDs
Public title
An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients
Scientific 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
Secondary ID [1] 0 0
2018-000022-66
Secondary ID [2] 0 0
16-HMedIdeS-12
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Kidney Transplant Rejection 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Imlifidase
Other interventions - Plasma Exchange

Experimental: Imlifidase - Subjects randomized to imlifidase treatment received one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes.

Active comparator: 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.


Treatment: Drugs: Imlifidase
Imlifidase is an immunoglobulin G (IgG) degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity.

Other interventions: Plasma Exchange
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.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Start of treatment until 5 days following start of treatment
Secondary outcome [1] 0 0
Reduction in DSA Levels After Treatment
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Screening until Day 180
Secondary outcome [2] 0 0
Estimated Glomerular Filtration Rate (eGFR) Levels
Assessment method [2] 0 0
eGFR as calculated from p-creatinine is a measure of kidney function. eGFR was assessed at all visits throughout the study.
Timepoint [2] 0 0
Screening until Day 180
Secondary outcome [3] 0 0
Urine Albumine/Creatinine Ratio
Assessment method [3] 0 0
The albumine/creatinine ratio in urine is a measure of kidney function.
Timepoint [3] 0 0
Pre-dose until Day 180
Secondary outcome [4] 0 0
Number of Patients With Graft Loss Within 180 Days of Treatment
Assessment method [4] 0 0
Information on patients who experienced graft loss was collected throughout the study.
Timepoint [4] 0 0
Screening until Day 180
Secondary outcome [5] 0 0
Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180
Assessment method [5] 0 0
Biopsies collected 180 days after treatment were analysed for signs of glomerulopathy.
Timepoint [5] 0 0
Day 180
Secondary outcome [6] 0 0
Number of Patients With Different Types of Kidney Histopathology Throughout the Trial
Assessment method [6] 0 0
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
Timepoint [6] 0 0
Screening, Day 29 and Day 180
Secondary outcome [7] 0 0
Number of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels
Assessment method [7] 0 0
Kidney biopsies were taken at screening, Day 29, and Day 180. Changes from baseline in mRNA levels were assessed as evidence of resolved AMR.
Timepoint [7] 0 0
Screening, Day 29, and Day 180
Secondary outcome [8] 0 0
Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions
Assessment method [8] 0 0
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.
Timepoint [8] 0 0
Day 1 to Day 180
Secondary outcome [9] 0 0
Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg)
Assessment method [9] 0 0
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.
Timepoint [9] 0 0
Pre-dose until Day 6
Secondary outcome [10] 0 0
Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg
Assessment method [10] 0 0
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.
Timepoint [10] 0 0
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)
Secondary outcome [11] 0 0
DSA Functionality Determined by C1q Analysis Pre- and Post-treatment
Assessment method [11] 0 0
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.
Timepoint [11] 0 0
Screening until Day 6
Secondary outcome [12] 0 0
Pharmacokinetic (PK) Profile of Imlifidase: Cmax
Assessment method [12] 0 0
Cmax = Maximum observed plasma concentration of imlifidase following dosing
Timepoint [12] 0 0
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
Secondary outcome [13] 0 0
PK Profile of Imlifidase: Tmax
Assessment method [13] 0 0
Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
Timepoint [13] 0 0
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
Secondary outcome [14] 0 0
PK Profile of Imlifidase: t1/2
Assessment method [14] 0 0
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).
Timepoint [14] 0 0
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
Secondary outcome [15] 0 0
PK Profile of Imlifidase: AUC
Assessment method [15] 0 0
Area under the imlifidase plasma concentration vs time curve (AUC)
Timepoint [15] 0 0
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
Secondary outcome [16] 0 0
PK Profile of Imlifidase: CL
Assessment method [16] 0 0
Clearance (CL) of imlifidase means the volume of blood cleared of imlifidase per unit of time.
Timepoint [16] 0 0
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
Secondary outcome [17] 0 0
PK Profile of Imlifidase: Volume of Distribution (V)
Assessment method [17] 0 0
Vss = volume of distribution associated with steady state VZ = volume of distribution associated with the elimination phase
Timepoint [17] 0 0
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
Secondary outcome [18] 0 0
Concentration of Anti-drug Antibodies (ADAs)
Assessment method [18] 0 0
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.
Timepoint [18] 0 0
Screening until Day 180

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
30/04/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
16/11/2022
Sample size
Target
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
The Royal Melbourne Hospital - Melbourne
Recruitment hospital [2] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 0 0
Royal Prince Alfred Hospital - Sydney
Recruitment postcode(s) [1] 0 0
3050 - Melbourne
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment postcode(s) [3] 0 0
- Sydney
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
Minnesota
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
Austria
State/province [5] 0 0
Vienna
Country [6] 0 0
France
State/province [6] 0 0
Bordeaux
Country [7] 0 0
France
State/province [7] 0 0
Grenoble
Country [8] 0 0
France
State/province [8] 0 0
Paris
Country [9] 0 0
Germany
State/province [9] 0 0
Berlin
Country [10] 0 0
Germany
State/province [10] 0 0
Hannover

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hansa Biopharma AB
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Operations
Address 0 0
Hansa Biopharma AB
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT03897205