Clinical trial NCT05369975: Efficacy and Safety in Imlifidase Desensitized Kidney Tx Patients, Including Two Non-Comparative Reference Cohorts
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Kidney Transplantation in Highly Sensitized Patients
Keywords: Desensitization
Highly sensitized
Positive crossmatch
Unlikely to be transplanted
Renal transplantation
Kidney transplantation
Deceased donor
End-Stage Renal Disease
ESRD
Lead sponsor: Hansa Biopharma AB
Sponsor class: INDUSTRY
First posted: 2022-05-11
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label, non-randomised trial in highly sensitized adult kidney transplant patients with positive XM against an available deceased donor.

The rational for a non-randomised trial is that no other effective or approved desensitization protocol exists in deceased-donor kidney transplantation that would provide a suitable control.

A non-comparative concurrent reference cohort from participating sites will be included to address differences in-site practice and experience.

A non-comparative historical reference cohort from the CTS registry will be included to address the outcome in a less sensitized patient group.
Primary purpose: TREATMENT

Brief summary: 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.

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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Graft failure-free survival 1 year after transplantation following imlifidase treatment
timeFrame: 12 months after transplantation
Secondary outcomes:
measure: Graft failure-free survival 1 year after transplantation in non-comparative concurrent reference cohort
timeFrame: 12 months after transplantation
measure: Renal function up to 1 year after transplantation
timeFrame: Screening, pre-imlifidase, 24, 48 and 72 hours, Days 5, 6, 8, 10 and 15, at 1, 3 and 6 months and at 1 year
measure: Patient survival at 1 year after transplantation
timeFrame: 12 months after transplantation
measure: Graft survival at 1 year after transplantation
timeFrame: 12 months after transplantation
measure: Proportion of patients with conversion of a positive XM test to negative within 24 hours after imlifidase treatment
timeFrame: Pre-imlifidase, 2, 4 and 24 hours post-imlifidase.
measure: HLA/DSA antibody levels up to 1 year after imlifidase treatment
timeFrame: Screening, pre-imlifidase, at 2, 4, 24, 48 and 72 hours, at Days 5, 6, 8, 15, at 1, 3 and 6 months, and at 1 year
measure: Imlifidase pharmacokinetics (AUC)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacokinetics (Cmax)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacokinetics (tmax)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacokinetics (t1/2)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacokinetics (CL)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacokinetics (Vz)
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, 10, and 15
measure: Imlifidase pharmacodynamics
timeFrame: Pre-imlifidase, 30 minutes and 2, 4, 8, 24, 48 and 72 hours, Days 5, 6, 8, and 10
measure: Anti-drug antibodies (ADA) levels up to 1 year after imlifidase treatment
timeFrame: Days 8, and 15, at 1, 3 and 6 months, and at 1 year
measure: Frequency of delayed graft function (DGF)
timeFrame: Up to 7 days after transplantation
measure: Proportion of patients with biopsy- and serology (DSA)-confirmed antibody-mediated rejections (AMRs)
timeFrame: Up to 12 months after transplantation
measure: Proportion of patients with biopsy- and serology (DSA)-confirmed cell-mediated rejections (CMRs)
timeFrame: Up to 12 months after transplantation
measure: Proportion of patients with infusion-related reactions within 48 hours of imlifidase infusion
timeFrame: Up to 48 hours after transplantation
measure: Proportion of patients with severe or serious infections within 30 days after transplantation
timeFrame: Up to 30 days after transplantation
measure: Change in patient-reported life participation
timeFrame: Screening and at 1 year
measure: Proportion of patients with rejection episodes (AMRs and CMRs) during the first post-transplant year in patients with a functioning graft at the end of the first post-transplant year
timeFrame: From transplantation to 1 year
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medizinische Universitaet Wien
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg
city: Prague
country: Czechia
facility: Institut klinicke a experimentalni mediciny (IKEM)
city: Bois Guillaume
country: France
facility: Centre Hospitalier Universitaire (CHU) de Rouen - Hôpital de Bois-Guillaume
city: La Tronche
country: France
facility: CHU de Grenoble - Hôpital Michallon
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Munich
country: Germany
facility: Klinikum rechts der Isar der Technische Universitaet Muenchen
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Parma
country: Italy
facility: Azienda Ospedaliero - Universitaria di Parma
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Ljubljana
country: Slovenia
facility: Department of Nephrology , Zaloška 7
city: Barcelona
country: Spain
facility: Hospital Del Mar, Servicio de Nefrología
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona, Unidad de Trasplante Renal
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital (HUVH)
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Huddinge
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Leeds
country: United Kingdom
facility: St. James University Hospital
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
Study officials:
affiliation: Hansa Biopharma AB
name: Clinical Operations
role: STUDY_DIRECTOR
References: