Imlifidase Prior to Kidney Transplant in Highly Sensitised Children

Phase 2RecruitingNCT05753930

Hansa Biopharma AB10 enrolled

Overview

The goal of this clinical trial is to learn about the efficacy and safety of imlifidase in highly sensitized paediatric patients, 1-17 years old, with end stage renal disease (ESRD). The main questions it aims to answer are: * Does imlifidase treatment result in crossmatch conversion that enables transplantation? * How is the function of the transplanted kidney? The participants will be hospitalised in accordance with the normal routines for transplanted patients. The patients will receive medication to prevent rejection of the donor kidney, and because such treatment make the body more vulnerable medications to prevent infections.

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. The trial will include highly sensitised ESRD paediatric patients (1-17 years). The patients have previously undergone desensitization unsuccessfully or have an anti-HLA antibody status deemed too difficult to make a successful desensitization using other experimental methods. A screening visit will take place when an organ offer has been placed for a final check of the patients' eligibility for study participation. All patients included in the trial will be desensitized with imlifidase to convert the positive XM to negative and then transplanted with either a kidney from a deceased donor (DD) or a living donor (LD). Patients will be hospitalised in accordance with the normal routines for transplanted patients at each clinic. Following transplantation, the patients will receive induction therapies, rejection prophylaxis, and maintenance immunosuppressive therapies. The patients will be closely monitored for any signs of antibody-mediated rejections (AMRs). The duration of the interventional trial period after an organ has been offered will be 6 months for each patient. The trial includes a follow-up part to collect long-term efficacy and safety data up to 5 years after the transplantation.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 1 YearMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Signed Informed Consent obtained from patient/parent/legal guardian/independent witness (depending on patient's age) before any trial-related procedures 2. Highly sensitised patient with panel reactive antibodies (PRA) ≥80% 3. Male or female patient between the age of 1 to 17 years (up to the day before the 18th birthday) at the time of screening 4. Patient with end-stage renal disease (ESRD) and waiting for a renal transplant from a living or deceased donor 5. Patient must be transplantable (including size mismatch) at the time of obtaining informed consent for trial participation 6. Patients who have previously undergone desensitisation unsuccessfully with plasmapheresis/IVIg/anti-CD20 or have an anti-HLA antibody status deemed too difficult to make a successful desensitisation (judgement based on physicians' previous experience with similar patients) 7. Positive crossmatch (XM) test determined by flow cytometry crossmatch (FCXM) and/or complement-dependent cytotoxicity crossmatch (CDCXM) tests against the donor. For the DD patients, if physical XM tests are not practically possible due to lack of time, patients may be included on a virtual crossmatch (vXM) predictive of a positive XM test. 8. Willingness and ability to comply with the protocol as judged by the investigator Exclusion Criteria: 1. Previous treatment with imlifidase 2. IVIg treatment within 28 days prior to imlifidase treatment 3. Desensitisation treatment(s) within 1 month prior to the current transplantation 4. Hypersensitivity to the active substance (imlifidase) or to any of the excipients and to other immunosuppressive drugs specified in the protocol 5. Ongoing serious infections 6. Present, or history of, thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP 7. At the time of transplantation: severe other condition requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease, active peripheral vascular disease, proven hypercoagulable conditions/events or oxygen dependent respiratory disease 8. Malignancy within 3 years prior to transplantation 9. ABO blood group incompatible transplantations (A2 and A2B kidneys will not be accepted for B recipients) 10. Any other reason that, in the view of the investigator, precludes transplantation 11. Breast feeding or pregnancy, if applicable 12. Woman of fertile age and sexually active without adequate contraceptive measures to avoid pregnancy during the interventional trial period (i.e. up to 6 months after transplantation) 13. Suspicion of Covid-19 infection or positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test 14. Positive serology for human immunodeficiency virus (HIV) 15. Clinical signs of hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), or Epstein Barr virus (EBV) infection 16. Donor with positive serology for HIV, HBV, HCV, CMV or EBV to a patient with negative serology (mismatch serology) 17. Clinically relevant active infection(s) as judged by the investigator 18. Tuberculosis or history of tuberculosis 19. Use of other investigational agents within 5 terminal elimination half-lives prior to the transplantation 20. Contemporaneous participation in medical device studies 21. Known mental incapacity or language barriers precluding patients'/parents'/legal guardians' adequate understanding of the informed consent information and the trial activities 22. Inability by the judgement of the investigator to participate in the trial for any other reason

Outcomes

Primary Outcomes

Proportion of patients with conversion of a positive crossmatch test to negative within 24 hours after start of imlifidase treatment

Immunoglobulins (IgG) including donor specific antibodies (DSAs) are rapidly and efficiently cleaved by imlifidase. A conversion of a positive to a negative XM will enable transplantation.

Time frame: From start of imlifidase administration to 24 hours

Secondary Outcomes

Renal function up to 5 years after transplantation as assessed by estimated glomerular filtration rate (eGFR)

eGFR is a measure of kidney function. Reduced kidney function is characterised by a decreased eGFR value.

Time frame: From pre-dose imlifidase up to 5 years

Renal function up to 5 years after transplantation as assessed by serum/plasma creatinine levels

Creatinine is a measure of kidney function. Reduced kidney function is characterised by an increased value.

Time frame: From pre-dose imlifidase up to 5 years

Renal function up to 5 years after transplantation as assessed by serum/plasma cystatin C levels

Cystatin C is a measure of kidney function. Reduced kidney function is characterised by an increased value.

Time frame: From pre-dose imlifidase up to 5 years

Renal function up to 5 years after transplantation as assessed by proteinuria

Proteinuria (protein/creatinine ratio in urine) is a measure of kidney function. Reduced kidney function is characterised by an increased value.

Time frame: From pre-dose imlifidase up to 5 years

DSA levels up to 5 years after transplantation

Donor specific antibodies (DSAs) are antibodies in the recipient directed against the transplanted organ.

Time frame: From pre-dose imlifidase up to 5 years

Graft survival (death censored) up to 5 year after transplantation

Time frame: From 6 months up to 5 years

Graft failure-free survival up to 5 years after transplantation

Time frame: From 6 months up to 5 years

Patient survival up to 5 years after transplantation

Time frame: From 6 months up to 5 years

Frequency of delayed graft function (DGF)

DGF is defined as 'Need for dialysis within 7 days of transplantation' in "Delayed graft function in kidney transplantation: developing drugs for prevention, guidance for industry", FDA 2019. Frequency of patients having DGF in accordance with this definition will be presented.

Time frame: From transplantation up 7 days after transplantation

Length of DGF

DGF is defined as 'Need for dialysis within 7 days of transplantation' in "Delayed graft function in kidney transplantation: developing drugs for prevention, guidance for industry", FDA 2019. The duration of DGFs in accordance with this definition will be presented.

Time frame: From transplantation up 7 days after transplantation

Proportion of patients with dialysis dependency up to 5 years after transplantation

Time frame: From 6 months up to 5 years

Imlifidase Pharmacokinetics (AUC)

AUC = Area under the imlifidase plasma concentration versus time curve.

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacokinetics (Cmax)

Cmax = Maximum observed plasma concentration of imlifidase following dosing.

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacokinetics (tmax)

tmax = Time point for maximum observed plasma concentration of imlifidase following dosing

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacokinetics (t1/2)

t1/2 = Terminal half-life of imlifidase.

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacokinetics (CL)

CL = Clearance of imlifidase.

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacokinetics (Vz)

Vz = Volume of distribution during the elimination phase

Time frame: From pre-dose imlifidase up to Day 15

Imlifidase Pharmacodynamic (PD) profile up to 9 days after imlifidase treatment

PD is assessed as serum concentrations of intact IgG and its fractions following infusion.

Time frame: From pre-dose imlifidase up to Day 10

Immunogenicity profile of imlifidase up to 5 years after imlifidase treatment

Immunogenicity is assessed as serum concentration of anti-imlifidase IgG (ADA).

Time frame: From pre-dose imlifidase up to 5 years

Proportion of patients with biopsy- and serology (DSA)-confirmed AMR up to 5 years after transplantation

Banff scores (Loupy et al. 2020) will be used for biopsy evaluation.

Time frame: From transplantation up to 5 years

Proportion of patients with biopsy confirmed cell-mediated rejection (CMR) up to 5 years after transplantation

Banff scores (Loupy et al. 2020) will be used for biopsy evaluation.

Time frame: From transplantation up to 5 years

Imlifidase Prior to Kidney Transplant in Highly Sensitised Children

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts