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Renal Function in Highly Sensitized Patients 1 Year After Desensitization With Imlifidase Prior to DD Kidney Tx (ConfIdeS)

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ClinicalTrials.gov Identifier: NCT04935177
Recruitment Status : Recruiting
First Posted : June 22, 2021
Last Update Posted : December 8, 2021
Sponsor:
Information provided by (Responsible Party):
Hansa Biopharma AB

Tracking Information
First Submitted Date  ICMJE June 14, 2021
First Posted Date  ICMJE June 22, 2021
Last Update Posted Date December 8, 2021
Actual Study Start Date  ICMJE October 14, 2021
Estimated Primary Completion Date July 30, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 21, 2021)
Mean estimated glomerular filtration rate (eGFR) at 12 months [ Time Frame: 12 months after randomization ]
eGFR is a measure of kidney function and will be compared between treatment arms. eGFR will be calculated based on p-creatinine according to the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is 90 mL/min/1.73m2. Kidney disease is characterised by a decreased eGFR value. For randomized patients who do not undergo transplantation, lose their graft or die before 12 months, eGFR will be set to zero, consistent with kidney failure.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 21, 2021)
Patient survival at 12 months [ Time Frame: 12 months after randomization ]
Patient survival will be summarized by end of trial and compared between treatment arms.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 21, 2021)
  • Frequency of dialysis dependency at 12 months [ Time Frame: 12 months after randomization ]
    Dialysis dependency is a measure of kidney function. A comparison between treatment arms will be done. Patients who are lost to follow up will be imputed as being dialysis-dependent.
  • Graft failure-free survival at 12 months [ Time Frame: 12 months after randomization ]
    Graft failure-free survival is defined as the time from randomization to the first of either graft loss or death and will be compared between treatment arms.
  • Graft survival at 12 months [ Time Frame: 12 months after randomization ]
    Graft survival will be compared between treatment arms in transplanted patients. Time to graft loss will be presented.
  • Frequency of wait-list categories at 12 months [ Time Frame: 12 months after randomization ]
    Frequency of patients on different wait-list categories (i.e. on waitlist, temporarily delisted, delisted, dead) will be summarized by randomized treatment group
  • Frequency of delayed graft function [ Time Frame: Within 7 days after transplantation ]
    Delayed graft function is defined as need for dialysis within 7 days of transplantation. Delayed graft function will be summarized by randomized treatment group
  • Antibody-mediated rejection (AMR) frequency [ Time Frame: During 12 months after randomization ]
    Confirmed AMRs will be summarized by treatment. Presumed/suspected AMRs not confirmed with biopsies will be recorded as AE/SAE.
  • Cell-mediated rejection (CMR) frequency [ Time Frame: During 12 months after randomization ]
    Confirmed CMRs will be summarized by treatment. Presumed/suspected CMRs not confirmed with biopsies will be recorded as AE/SAE.
  • Conversion of positive crossmatch test to negative [ Time Frame: Within 4 hours after imlifidase treatment ]
    Imlifidase is highly efficacious in converting a positive crossmatch test to a negative. This outcome will be assessed for patients treated with imlifidase.
  • Donor specific antibody (DSA) levels for all antibodies with a mean fluorescence intensity (MFI) of ≥1000 [ Time Frame: Prior first dose, 2, 4, 24, 48, 72 h and Days 5, 6, 8,15 and Months 1, 3, 6, 8, 10, and 12 ]
    Analysis of DSAs will be done in serum from patients randomized to imlifidase using an IgG single antigen solid-phase immunoassay (SAB-HLA). Least square mean and standard error of DSA levels will be displayed over time.
  • Anti-drug antibodies (ADA) [ Time Frame: Prior first dose, 48 hours, Days 8, 15, and Months 1, 2, 3, 6, 8, 10, and 12 ]
    Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis.
  • Imlifidase pharmacokinetics (AUC) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    AUC = Area under the imlifidase plasma concentration versus time curve
  • Imlifidase pharmacokinetics (Cmax) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    Cmax = Maximum observed plasma concentration of imlifidase following dosing
  • Imlifidase pharmacokinetics (tmax) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    tmax = Time point for maximum observed plasma concentration of imlifidase following dosing
  • Imlifidase pharmacokinetics (t1/2) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    t1/2 = Terminal half-life of imlifidase
  • Imlifidase pharmacokinetics (CL) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    CL = Clearance of imlifidase
  • Imlifidase pharmacokinetics (Vz) [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 15 ]
    Vz = Apparent volume of distribution during terminal phase
  • Imlifidase pharmacodynamics [ Time Frame: Within 24 hours prior to imlifidase treatment and up to Day 10 ]
    Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done.
  • Safety as measured by adverse events (AEs) [ Time Frame: From signing informed consent to 12 months ]
    Safety is assessed as type, frequency and intensity of adverse events (AEs)/Serious adverse events (SAEs) including clinically relevant changes in clinical laboratory tests, vital signs and ECG)
  • Safety as measured by serious adverse events (SAEs) [ Time Frame: From signing informed consent to 12 months ]
    Safety is assessed as type and frequency serious adverse events (SAEs)
  • Safety as measured by other adverse events (AEs) [ Time Frame: From signing informed consent to 12 months ]
    Safety is assessed as type and frequency of other adverse events (AEs) - i.e. not including SAEs
  • Change in patient-reported life participation, as measured by PROMIS-SF-8a [ Time Frame: At pre-screening and at 12 months after randomization ]
    The PROMIS Social Health domain "Ability to participate in social roles & activities PROMIS-SF-8" will be used as a measure of the patients' health related quality of life.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Renal Function in Highly Sensitized Patients 1 Year After Desensitization With Imlifidase Prior to DD Kidney Tx
Official Title  ICMJE An Open-label, Controlled, Randomized Phase 3 Trial Evaluating 12-month Kidney Function in Highly Sensitized (cPRA ≥99.9%) Kidney Tx Patients With Positive XM Against a Deceased Donor, Comparing Desensitization Using Imlifidase With SoC
Brief Summary An open-label, controlled, randomized Phase 3 trial evaluating 12-month kidney function in highly sensitized (cPRA ≥99.9%) kidney transplant patients with positive crossmatch against a deceased donor, comparing desensitization using imlifidase with standard of care
Detailed Description

After being informed about the study and potential risks, all patients giving written informed consent will undergo pre-screening to determine eligibility for study entry.

Once an organ offer is received, a virtual crossmatch (vXM) is performed. If the crossmatch is considered predictive of a positive flow cytometry crossmatch (FCXM), the patient will be evaluated if eligible to receive the desensitization currently in use at the study site. Subsequently the patient will be randomized in a 1:1 ratio to the imlifidase or the control arm.

If the patient is randomized to the imlifidase arm, the organ will be accepted and shipped, and the patient will proceed to imlifidase treatment (generally within 24 h prior to transplantation) followed by transplantation. If the patient is randomized to the control arm, transplantation made possible by the local desensitization regimen will occur. If the institution-specific desensitization protocol is deemed not to be successful, the organ offer will be turned down, and the patient will remain active on the waiting list and remain in the trial, while the kidney will be allocated to another recipient through the kidney allocation system (KAS).

All transplanted patients will receive induction therapy and maintenance immunosuppression. All patients will be followed for 12 months.

Estimated glomerular filtration rate (eGFR) will be assessed 12 months after randomization as the primary endpoint reasonably likely to predict a clinical benefit in patient survival.

All patients with donor specific antibodies (DSA) are at risk of developing antibody-mediated rejection (AMR). Imlifidase removes DSA quickly and efficiently at the time of transplantation but, as with other desensitization methods, the antibodies are expected to re-occur after transplantation. In the imlifidase treatment arm, and for desensitized control arm patients, protocol kidney biopsies will be performed at the time of transplantation and at 1 year after transplantation.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Open-label, controlled and randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplantation in Highly Sensitized Patients
Intervention  ICMJE
  • Drug: Imlifidase
    Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly selective towards IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG.
    Other Name: IdeS, HMED-IdeS
  • Procedure: PLEX
    PLEX is performed according to the respective site's standard procedure for desensitization.
    Other Name: Plasma exchange, PE
  • Drug: IVIg
    IVIg prepared from a pool of immunoglobulins from the plasma of thousands of healthy donors is administered in accordance with respective site's standard procedure for desensitization.
    Other Name: Intravenous immunoglobulin
  • Drug: Anti-CD20 antibodies
    Rituximab and other anti-CD20 according to the respective site's standard procedure for desensitization.
    Other Name: Rituximab
  • Drug: Eculizumab
    Eculizumab according to the respective site's standard procedure for desensitization.
    Other Name: Soliris
  • Other: Remain on wait list
    Remain on wait list for a more compatible organ offer if desentization with institutional protocol is not appropriate
Study Arms  ICMJE
  • Experimental: Imlifidase
    Imlifidase, is provided as a freeze-dried powder for concentrate for solution for infusion, 11 mg per vial. After reconstitution with sterile water for injection, the concentrate contains 10 mg/mL imlifidase. Imlifidase is administered intravenously as one infusion of 0.25 mg/kg over 15 minutes generally 24 hours prior to transplantation. A second dose of 0.25 mg/kg may be given if the first imlifidase dose is considered not to have had sufficient effect.
    Intervention: Drug: Imlifidase
  • Best available treatment
    Institution-specific desensitization protocol (i.e. any combination of plasma exchange (PLEX), intravenous IVIg, anti-CD20 antibody, and eculizumab) where appropriate OR remain on wait list for a more compatible organ offer
    Interventions:
    • Procedure: PLEX
    • Drug: IVIg
    • Drug: Anti-CD20 antibodies
    • Drug: Eculizumab
    • Other: Remain on wait list
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: June 21, 2021)
64
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 30, 2023
Estimated Primary Completion Date July 30, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Signed Informed Consent obtained before any trial-related procedures
  • Male or female age 18-70 years at the time of screening
  • Chronic kidney disease (CKD) stage 5, highly sensitized as evaluated by standard selection criteria, and active on the OPTN waiting list for a DD kidney transplant
  • Original calculated panel reactive antibody (cPRA) ≥99.9%
  • Virtual crossmatch (vXM), predictive of a positive crossmatch to an available deceased donor (DD)
  • Willingness and ability to comply with the protocol
  • Willingness to participate in the planned 4-year extension trial

Exclusion Criteria:

  • High dose IVIg (2 g/kg) treatment within 28 days prior to imlifidase treatment
  • Previous treatment with imlifidase
  • Breast feeding or pregnancy
  • Women of child-bearing potential not willing or able to practice FDA-approved forms of contraception, or abstinence. Two medically acceptable methods of highly effective contraception must be used for the duration of the study (e.g. oral, transdermal, intravaginal, injectable or implantable contraceptive; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; bilateral tubal occlusion; or double barrier method). For a woman to be considered postmenopausal this ascertainment must be made according to medical records and clinical history and may be aided by measurement of elevated postmenopausal serum gonadotropin levels (FSH).
  • ABO blood group incompatible transplantations (A2 or A2B kidneys will not be accepted for B recipients)
  • Positive serology for human immunodeficiency virus (HIV)
  • Clinical signs of hepatitis B virus (HBV) or hepatitis C virus (HCV) infections
  • Clinical signs of cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections
  • Positive test for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (according to local hospital routines)
  • Active tuberculosis
  • Severe other conditions requiring treatment and close monitoring, e.g. cardiac failure ≥grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent chronic obstructive pulmonary disease (COPD)
  • Any condition that in the view of the Investigator precludes transplantation
  • History of a proven hypercoagulable condition
  • Present or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
  • Intake of investigational drugs within 5 half-lives of the drug or 3 months, whichever is the longest
  • Contemporaneous participation in a medical device study
  • Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities
  • Inability by the judgement of the investigator to participate in the trial for any other reason
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04935177
Other Study ID Numbers  ICMJE 20-HMedIdeS-17
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: Clinical Operations Hansa Biopharma AB
PRS Account Hansa Biopharma AB
Verification Date December 2021

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