Efficacy and Safety in Imlifidase Desensitized Kidney Tx Patients, Including Two Non-Comparative Reference Cohorts

A Controlled, Open-label PA Efficacy and Safety Study in Imlifidase Desensitised Kidney Tx Patients With Positive XM Against a Deceased Donor Prior to Imlifidase Treatment, Including Non-comparative Registry and Concurrent Reference Cohorts

An open-label post authorization efficacy and safety study evaluating graft failure-free survival at 1-year in highly sensitized end-stage renal disease (ESRD) patients with positive crossmatch (XM) against a deceased donor prior to desensitized with imlifidase and subsequent kidney transplantation. Two non-comparative reference cohorts are included to assess the impact of differences in post-transplantation management and outcome in less sensitized patients.

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. All highly sensitized ESRD patients with a positive XM will be desensitized with imlifidase to convert the XM to negative and then transplanted. Following transplantation, patients will receive induction therapies (corticosteroids, rabbit anti-human thymocyte immunoglobulin (rATG)), rejection prophylaxis (high-dose intravenous immunoglobulin (IVIg), rituximab or biosimilar) and maintenance immunosuppressive therapies. The patients will be followed for 12 months.

The efficacy of imlifidase per se, i.e. rapidly cleavage of IgG to enable transplantation, is not reflected by the important clinical outcomes 1-year graft failure-free survival and kidney function. These are instead a measure of effectiveness and safety in the real-world transplantation setting. It should be noted that patient outcome is highly dependent on the post-transplantation management, as well as compliance to maintenance immunosuppressive therapy.

All patients with donor specific antibodies (DSAs) are at risk for antibody-mediated reactions (AMRs). 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. The highly sensitized patients included in this trial must therefore be closely monitored for any signs of AMR. Protocol kidney biopsies will be performed at 6 months and 1 year after transplantation. For-cause biopsies, DSA and estimated glomerular filtration rate (eGFR) will be collected to assess AMR frequency.

A non-comparative concurrent reference cohort consisting of kidney transplanted patients from participating trial sites with any grade of sensitization and a negative XM towards their donor will be included in the trial to address differences in-site practice, experience, and amount of immunosuppressive therapies given that may have an impact on the overall results for the imlifidase-treated cohort. Once a highly sensitized imlifidase treated patient has been transplanted at a site, subsequent patients who are offered a compatible kidney will be offered the opportunity to be included in the trial as part of the reference cohort group and transplanted. The goal is to have at least 1 or 2 patients from each site participating in the non-comparative concurrent reference cohort. Given that the patients in this cohort will be qualitatively different from the imlifidase treated patients, formal statistical comparisons will not be appropriate. Patients included in the non-comparative concurrent reference cohort will be followed for 12 months after transplantation and treated in accordance with each clinic's normal transplantation routines.

A second, non-comparative historical reference cohort of 100 kidney transplanted patients will be randomly selected from the Collaborative Transplant Study (CTS) registry in accordance with the inclusion and exclusion criteria provided in the protocol prior to commencement of the active trial. No clinical activities will be done to this historical reference cohort. The patients of this cohort will be less sensitized compared to the imlifidase-treated cohort, have a negative XM towards their donor and have been transplanted during 2010 or later. Since patients in this cohort are expected to have both a better prognosis and a higher graft survival rate at 1 year than the imlifidase-treated patients, formal statistical comparison between the groups would be inappropriate. The year 2010 was chosen as cut-off for inclusion in the non-comparative historical reference cohort to make it likely that the patients in this group have received the same maintenance immunosuppression as is given today to most kidney transplant recipients.

Inclusion Criteria:

Inclusion criteria for ALL patients

1. Male or female patient aged 18-75 years
2. ABO-compatible deceased donor aged 10-70 years

Inclusion criteria for IMLIFIDASE patients

1. ESRD active on the renal transplant waiting list of a kidney allocation system at the time of screening
2. High sensitization with the highest unmet medical need unlikely to be transplanted under the available kidney allocation system including prioritisation programmes for highly sensitized patients
3. Known DSA against an available deceased donor
4. Positive crossmatch test determined by complement-dependent cytotoxicity crossmatch (CDCXM) and/or flow cytometric crossmatch (FCXM) against an available deceased donor. 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.
5. Signed Informed Consent obtained before any trial-related procedures
6. Willingness and ability to comply with the protocol

Inclusion criteria for patients in the NON-COMPARATIVE CONCURRENT REFERENCE COHORT

1. Active on the renal transplant waiting list at a participating trial site at the time of screening
2. An acceptable kidney transplant from a deceased donor
3. Signed Informed Consent obtained before any trial related procedures
4. Willingness and ability to comply with the protocol

Inclusion criteria for patients in the NON-COMPARATIVE HISTORICAL REFERENCE COHORT

1. ESRD with a kidney transplant from a deceased donor
2. Being transplanted in Europe after 01-Jan-2010 and included in the CTS registry
3. Panel reactive antibodies (PRA) ≥ 50% (CDC T- or B-cell PRA, calculated panel reactive antibodies (cPRA), or virtual panel reactive antibodies (vPRA))
4. Maintenance immunosuppression (intention to treat) with calcineurin inhibitor, mycophenolate mofetil (MMF) and corticosteroids in combination

Exclusion Criteria:

Exclusion criteria for IMLIFIDASE patients and for patients in the NON-COMPARATIVE CONCURRENT REFERENCE COHORT

1. Use of investigational agents within 5 terminal elimination half-lives prior to the transplantation
2. Malignancy within 5 years prior to transplantation
3. Positive serology for human immunodeficiency virus (HIV)
4. Clinically relevant active infection(s) as judged by the investigator
5. Contemporaneous participation in medical device studies
6. Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities
7. Inability by the judgement of the investigator to participate in the trial for any other reason

Exclusion criteria for IMLIFIDASE patients

1. Previous treatment with imlifidase

2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase treatment

3. Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test

4. Breast feeding or pregnancy

5. Hypersensitivity to the active substance (imlifidase) or to any of the excipients

6. Ongoing serious infections

7. Present, or history of, thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP

8. Severe other condition requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent respiratory disease

9. Female of childbearing potential, not willing to use effective contraception during the 3 weeks following treatment with imlifidase. In the context of this trial, 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 such as:

   1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation; (i) oral, (ii) intravaginal, or (iii) transdermal
   2. progestogen-only hormonal contraception associated with inhibition of ovulation; (i) oral, (ii) injectable, or (iii) implantable
   3. intrauterine device (IUD)
   4. intrauterine hormone-releasing system (IUS)
   5. bilateral tubal occlusion
   6. vasectomised partner
   7. true abstinence: When this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]

10. Any other reason that, in the view of the investigator, precludes transplantation

Exclusion criteria for patients in the NON-COMPARATIVE HISTORICAL REFERENCE COHORT

1. Patients treated with mammalian target of rapamycin (mTOR) inhibitors
2. Patients treated with belatacept