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

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ClinicalTrials.gov Identifier: NCT03897205
Recruitment Status : Recruiting
First Posted : April 1, 2019
Last Update Posted : October 17, 2019
Sponsor:
Information provided by (Responsible Party):
Hansa Biopharma AB

Tracking Information
First Submitted Date  ICMJE March 27, 2019
First Posted Date  ICMJE April 1, 2019
Last Update Posted Date October 17, 2019
Actual Study Start Date  ICMJE April 30, 2019
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
Maximum DSA reduction within 5 days from start of treatment [ Time Frame: Start of treatment until 5 days following 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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03897205 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 28, 2019)
  • DSA levels up to 180 days after treatment [ Time Frame: Screening until Day 180 ]
    DSA levels will be assessed at all visits throughout the study.
  • HLA-antibodies levels up to 180 days after treatment [ Time Frame: Screening until Day 180 ]
    HLA-antibodies levels will be assessed at all visits throughout the study.
  • eGFR levels up to 180 days after treatment [ Time Frame: Screening until Day 180 ]
    eGFR as calculated from p-creatinine is a measure of kidney function. P-creatinine/eGFR will be assessed at all visits throughout the study.
  • Albumin/creatinine ratio in urine up to 180 days after treatment [ Time Frame: Screening until 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.
  • Proportion of subjects with graft loss within 180 days of treatment [ Time Frame: Screening until Day 180 ]
    Information on graft loss will be collected throughout the study and proportion of subjects with graft loss will be reported.
  • Proportion of subjects with signs of transplant glomerulopathy 180 days after treatment [ Time Frame: Day 180 ]
    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
  • Change from baseline in histopathology at day 29 and day 180 after treatment [ Time Frame: Screening, 29 days and 180 days after treatment ]
    Kidney biopsies will be assessed according to the Banff (2017) criteria pre-dose (screening) and at day 29 and 180.
  • Change from baseline in mRNA levels in kidney biopsies at day 29 and day 180 after treatment [ Time Frame: Screening, Day 29 and Day 180 ]
    Kidney biopsies will be taken at screening, day 29 and 180 and assessed for mRNA levels. Changes from baseline will be presented.
  • Safety as evaluated by AEs [ Time Frame: Start of treatment until Day 180 ]
    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.
  • Number of sessions with PE [ Time Frame: Start of treatment until Day 180 ]
    The number of PE sessions given throughout the study will be recorded in the CRF
  • Proportion of subjects with reduction of total serum IgG following treatment until administration of IVIg [ Time Frame: Start of treatment (Day 1) up to administration of IVIg on Day 4 ]
    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.
  • Proportion of subjects with no intact IgG following treatment until administration of IVIg. [ Time Frame: Start of treatment (Day 1) up to administration of IVIg on Day 4 ]
    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.
  • DSA functionality determined by C1q or C3d analysis pre- and post-treatment [ Time Frame: Screening until Day 180 ]
    Analysis of DSA functionality assessed as mean MFI levels will be done at all visits throughout the study.
  • PK profile of imlifidase: Cmax [ Time Frame: Start of treatment until Day 15 ]
    Cmax = Maximum observed plasma concentration of imlifidase following dosing
  • PK profile of imlifidase: Tmax [ Time Frame: Start of treatment until Day 15 ]
    Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
  • PK profile of imlifidase: t1/2 [ Time Frame: Start of treatment until Day 15 ]
    t1/2 = terminal half-life of imlifidase
  • PK profile of imlifidase: AUC [ Time Frame: Start of treatment until Day 15 ]
    AUC = Area under the imlifidase plasma concentration vs time curve
  • PK profile of imlifidase: CL [ Time Frame: Start of treatment until Day 15 ]
    CL = Clearance of imlifidase
  • PK profile of imlifidase: V [ Time Frame: Start of treatment until Day 15 ]
    V = Volume of distribution
  • Proportion of patients with anti-drug antibodies (ADAs) [ Time Frame: Screening until Day 180 ]
    Samples will be collected and analysed for presence anti-imlifidase IgE and anti-imlifidase IgG throughout the study.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients
Official Title  ICMJE 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
Brief Summary

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 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

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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplant Rejection
Intervention  ICMJE
  • Drug: Imlifidase
    Imlifidase is an IgG degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity.
    Other Name: HMED-IdeS, IdeS, IgG endopeptidase
  • Other: 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 (Igs) and then the plasma is passed back to the subject.
Study Arms  ICMJE
  • Experimental: Imlifidase
    Subjects randomized to imlifidase treatment will receive one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes.
    Intervention: Drug: Imlifidase
  • Active Comparator: Plasma Exchange
    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.
    Intervention: Other: Plasma Exchange
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 28, 2019)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date April 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Central Contact +46 46 16 56 70 clinicalstudyinfo@hansabiopharma.com
Listed Location Countries  ICMJE Australia,   Austria,   France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03897205
Other Study ID Numbers  ICMJE 16-HMedIdeS-12
2018-000022-66 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Hansa Biopharma AB
Study Sponsor  ICMJE Hansa Biopharma AB
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Elisabeth Sonesson, PhD Hansa Biopharma AB
PRS Account Hansa Biopharma AB
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP