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

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

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

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplantation in Highly Sensitized Patients
• Intervention / Treatment: Drug: Imlifidase; Procedure: PLEX; Drug: IVIg; Drug: Anti-CD20 antibodies; Drug: Eculizumab; Other: Remain on wait list

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: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Central Contact; Phone Number: +46 46 16 56 70; Email: clinicalstudyinfo@hansabiopharma.com

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • Recruiting
      • University of Alabama at Birmingham (UAB) Hospital
      • Principal Investigator: Douglas Anderson, MD
      • Contact: Douglas Anderson, MD; Email: douglasanderson@uabmc.edu
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Recruiting
      • Mayo Clinic Phoenix
      • Contact: H Khamash, MD; Email: Khamash.hasan@mayo.edu
      • Principal Investigator: H Khamash, MD
  • California
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
      • Contact: Stanley Jordan, MD; Email: Stan.Jordan@cshs.org
      • Principal Investigator: Stanley Jordan
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Keck Hospital of University of Southern California (USC)
      • Contact: Jim Kim, MD; Email: Jim.Kim@med.usc.edu
      • Principal Investigator: Jim Kim, MD
    • San Francisco, California, United States, 94143-0780
      • Recruiting
      • University of California San Francisco (UCSF) Medical Center
      • Contact: D Adey, MD; Email: Deborah.Adey@ucsf.edu
      • Principal Investigator: D Adey
    • San Francisco, California, United States, 94115
      • Recruiting
      • Sutter Health - California Pacific Medical Center
      • Contact: V Peddi, MD; Email: peddir@sutterhealth.org
      • Principal Investigator: V Peddi, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Terminated
      • Georgetown Transplant Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago Medical Center
      • Contact: P Witkowski, MD; Email: pwitkowski@surgery.bsd.uchicago.edu
      • Principal Investigator: P Witkowski, MD
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Derrick Christopher, MD; Email: derrick.christopher@nm.org
      • Principal Investigator: Derrick Christopher, MD
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Hospitals and Clinics
      • Contact: D Axelrod, MD; Email: david-axelrod@uiowa.edu
      • Principal Investigator: D Axelrod, MD
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • John Hopkins Hospital
      • Contact: N Desai, MD; Email: ndesai13@jhmi.edu
      • Principal Investigator: N Desai, MD
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: L Riella, MD; Email: lriella@mgh.harvard.edu
      • Principal Investigator: L Riella, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic Rochester
      • Contact: M Stegall, MD; Email: stegall.mark@mayo.edu
      • Principal Investigator: M Stegall
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: J Wellen, MD; Email: wellenj@wustl.edu
      • Principal Investigator: J Wellen
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Recruiting
      • Saint Barnabas Medical Center
      • Contact: A Patel, MD; Email: anup.patel@rwjbh.org
      • Principal Investigator: A Patel
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
      • Contact: Lloyd Ratner, MD; Email: lr2182@cumc.columbia.edu
      • Principal Investigator: Lloyd Ratner, MD
    • New York, New York, United States, 10016
      • Recruiting
      • New York University (NYU) Langone Transplant Institute
      • Contact: Bonnie A Lonze, MD; Email: Bonnie.Lonze@nyulangone.org
      • Principal Investigator: Bonnie Lonze, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania, Penn Medicine
      • Contact: R Parsons, MD; Email: ronald.parsons@pennmedicine.upenn.edu
      • Principal Investigator: R Parsons, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Hospital
      • Contact: Osama Gaber, MD; Email: AOGaber@houstonmethodist.org
      • Principal Investigator: A Gaber
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Methodist Hospital Specialty and Transplant
      • Contact: Matthias Kapturczak, MD; Email: matthias.kapturczak@hcahealthcare.com
      • Principal Investigator: Matthias Kapturczak, MD
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington Medical Center
      • Contact: N Leca, MD; Email: nleca@uw.edu
      • Principal Investigator: N Leca, MD
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Medical College of Wisconsin
      • Contact: M Cooper, MD; Email: macooper@mcw.edu
      • Principal Investigator: M Cooper

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: IdeS, HMED-IdeS
Other: 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	Procedure: PLEX; PLEX is performed according to the respective site's standard procedure for desensitization.; Other Names: 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 Names: Intravenous immunoglobulin; Drug: Anti-CD20 antibodies; Rituximab and other anti-CD20 according to the respective site's standard procedure for desensitization.; Other Names: Rituximab; Drug: Eculizumab; Eculizumab according to the respective site's standard procedure for desensitization.; Other Names: Soliris; Other: Remain on wait list; Remain on wait list for a more compatible organ offer if desentization with institutional protocol is not appropriate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean estimated glomerular filtration rate (eGFR) at 12 months	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.	12 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient survival at 12 months	Patient survival will be summarized by end of trial and compared between treatment arms.	12 months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of dialysis dependency at 12 months	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.	12 months after randomization
Graft failure-free survival at 12 months	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.	12 months after randomization
Graft survival at 12 months	Graft survival will be compared between treatment arms in transplanted patients. Time to graft loss will be presented.	12 months after randomization
Frequency of wait-list categories at 12 months	Frequency of patients on different wait-list categories (i.e. on waitlist, temporarily delisted, delisted, dead) will be summarized by randomized treatment group	12 months after randomization
Frequency of delayed graft function	Delayed graft function is defined as need for dialysis within 7 days of transplantation. Delayed graft function will be summarized by randomized treatment group	Within 7 days after transplantation
Antibody-mediated rejection (AMR) frequency	Confirmed AMRs will be summarized by treatment. Presumed/suspected AMRs not confirmed with biopsies will be recorded as AE/SAE.	During 12 months after randomization
Cell-mediated rejection (CMR) frequency	Confirmed CMRs will be summarized by treatment. Presumed/suspected CMRs not confirmed with biopsies will be recorded as AE/SAE.	During 12 months after randomization
Conversion of positive crossmatch test to negative	Imlifidase is highly efficacious in converting a positive crossmatch test to a negative. This outcome will be assessed for patients treated with imlifidase.	Within 4 hours after imlifidase treatment
Donor specific antibody (DSA) levels for all antibodies with a mean fluorescence intensity (MFI) of ≥1000	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.	Prior first dose, 2, 4, 24, 48, 72 h and Days 5, 6, 8,15 and Months 1, 3, 6, 8, 10, and 12
Anti-drug antibodies (ADA)	Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis.	Prior first dose, 48 hours, Days 8, 15, and Months 1, 2, 3, 6, 8, 10, and 12
Imlifidase pharmacokinetics (AUC)	AUC = Area under the imlifidase plasma concentration versus time curve	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacokinetics (Cmax)	Cmax = Maximum observed plasma concentration of imlifidase following dosing	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacokinetics (tmax)	tmax = Time point for maximum observed plasma concentration of imlifidase following dosing	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacokinetics (t1/2)	t1/2 = Terminal half-life of imlifidase	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacokinetics (CL)	CL = Clearance of imlifidase	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacokinetics (Vz)	Vz = Apparent volume of distribution during terminal phase	Within 24 hours prior to imlifidase treatment and up to Day 15
Imlifidase pharmacodynamics	Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done.	Within 24 hours prior to imlifidase treatment and up to Day 10
Safety as measured by adverse events (AEs)	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)	From signing informed consent to 12 months
Safety as measured by serious adverse events (SAEs)	Safety is assessed as type and frequency serious adverse events (SAEs)	From signing informed consent to 12 months
Safety as measured by other adverse events (AEs)	Safety is assessed as type and frequency of other adverse events (AEs) - i.e. not including SAEs	From signing informed consent to 12 months
Change in patient-reported life participation, as measured by PROMIS-SF-8a	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.	At pre-screening and at 12 months after randomization

Collaborators and Investigators

• Sponsor: Hansa Biopharma AB
• Investigators: Study Director: Clinical Operations, Hansa Biopharma AB

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2021
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: June 14, 2021
• First Submitted That Met QC Criteria: June 21, 2021
• First Posted (Actual): June 22, 2021

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Desensitization; Renal transplantation; Highly sensitized; Positive crossmatch; Unlikely to be transplanted; Deceased donor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Eculizumab
• Other Study ID Numbers: 20-HMedIdeS-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No