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

Sponsor

Hansa Biopharma AB (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04935177

Collaborator

(none)

Enrollment

Locations

Arms

26.5

Anticipated Duration (Months)

6.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplantation in Highly Sensitized Patients	Drug: Imlifidase Procedure: PLEX Drug: IVIg Drug: Anti-CD20 antibodies Drug: Eculizumab Other: Remain on wait list	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open-label, controlled and randomizedOpen-label, controlled and randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 14, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Mean estimated glomerular filtration rate (eGFR) at 12 months [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.

Secondary Outcome Measures

Patient survival at 12 months [12 months after randomization]
Patient survival will be summarized by end of trial and compared between treatment arms.

Other Outcome Measures

Frequency of dialysis dependency at 12 months [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 [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 [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 [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 [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 [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 [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 [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 [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) [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) [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) [Within 24 hours prior to imlifidase treatment and up to Day 15]
Cmax = Maximum observed plasma concentration of imlifidase following dosing
Imlifidase pharmacokinetics (tmax) [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) [Within 24 hours prior to imlifidase treatment and up to Day 15]
t1/2 = Terminal half-life of imlifidase
Imlifidase pharmacokinetics (CL) [Within 24 hours prior to imlifidase treatment and up to Day 15]
CL = Clearance of imlifidase
Imlifidase pharmacokinetics (Vz) [Within 24 hours prior to imlifidase treatment and up to Day 15]
Vz = Apparent volume of distribution during terminal phase
Imlifidase pharmacodynamics [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) [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) [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) [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham (UAB) Hospital	Birmingham	Alabama	United States	35249
2	Keck Hospital of University of Southern California (USC)	Los Angeles	California	United States	90033
3	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
4	Georgetown Transplant Institute	Washington	District of Columbia	United States	20007
5	Northwestern University	Chicago	Illinois	United States	60611
6	John Hopkins Hospital	Baltimore	Maryland	United States	21287
7	New York University (NYU) Langone Transplant Institute	New York	New York	United States	10016
8	Columbia University	New York	New York	United States	10032
9	Houston Methodist Hospital	Houston	Texas	United States	77030
10	Methodist Hospital Specialty and Transplant	San Antonio	Texas	United States	78229