This study has been transitioned to CTIS with ID 2024-511810-18-00 check the CTIS register for the current data. Primary objective• To determine the 1-year graft failure-free survival in highly sensitised kidney transplant patients, pre-treated with…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1-year graft failure-free survival in patients who have been kidney
transplanted after imlifidase treatment
Secondary outcome
• Renal function at several time points between 24 hours and 2 weeks and at 1,
3 and 6 months and 1 year after transplantation as assessed by
estimated glomerular filtration rate (eGFR) and serum/plasma creatinine levels
• Patient survival at 1 year after transplantation
• Graft survival at 1 year after transplantation
• Proportion of patients with conversion of a positive crossmatch test to
negative within 24 hours after imlifidase treatment
• HLA/DSA antibody levels at several time points between pre-dose imlifidase
and 2 weeks, and at 1, 3 and 6 months and 1 year after imlifidase
treatment
• Imlifidase PK up to 14 days after imlifidase treatment
• Imlifidase PD up to 9 days after imlifidase treatment
• ADAs up to 1 year after imlifidase treatment
• Frequency of DGF
• Proportion of patients with biopsy- and serology (DSA)-confirmed AMRs over 1
year
• Proportion of patients with biopsy confirmed CMRs over 1 year.
• Safety over 1 year as measured by reported SAEs
• Safety assessed as proportion of patients with infusion-related reactions
within 48 hours of imlifidase infusion
• Safety assessed as proportion of patients with severe or serious infections
within 30 days after transplantation
• Change in patient-reported life participation, as measured by the PROMIS
Social Health domain *Ability to participate in social roles & activities,
PROMIS-SF-8a*, from baseline to 1 year after transplantation
Secondary endpoints relating to the non-comparative concurrent reference cohort
• Graft failure-free survival at 1 year after transplantation
• Renal function at 1, 3 and 6 months and 1 year after transplantation as
assessed by eGFR and serum/plasma creatinine levels
• Patient survival at 1 year after transplantation
• Graft survival at 1 year after transplantation
• Frequency of DGF
• Proportion of patients with biopsy- and serology (DSA)-confirmed AMRs over 1
year
• Proportion of patients with biopsy confirmed CMRs over 1 year
• Safety over 1 year as measured by reported SAEs
• Safety assessed as proportion of patients with severe or serious infections
within 30 days after transplantation
• Change in patient reported life participation, as measured by the PROMIS
Social Health domain *Ability to participate in social roles & activities,
PROMIS-SF-8a*, from baseline to 1 year after transplantation
Secondary endpoints relating to the randomly selected non-comparative
historical reference cohort retrieved from the CTS registry
• Graft survival at 1 year after transplantation
• Renal function at 3 and 6 months, and 1 year as measured by serum/plasma
creatinine category (<130 µmol/L, 130-259 µmol/L, 260-400 µmol/L
and >400 µmol/L) (eGFR only available in selected patients)
• Patient survival at 1 year after transplantation
• 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 posttransplant year
Background summary
This controlled, non-randomised, open-label post-authorisation trial is
designed to provide comprehensive efficacy and safety data to support a full
marketing authorisation of imlifidase (Idefirix®) in EU. The trial will include
highly sensitised patients who will receive and accept crossmatch positive
kidney offers in line with the mode-of-action of imlifidase, i.e. conversion of
a positive crossmatch to a negative crossmatch. The patients to be included are
highly sensitised with the highest unmet medical need, unlikely to be
transplanted under the available kidney allocation system including
prioritisation programmes for highly sensitised patients. The primary objective
is to assess graft failure-free survival 1 year after
transplantation in patients desensitised with imlifidase prior to kidney
transplantation.
Kidney transplantation is considered the gold standard treatment of patients
with chronic kidney disease (CKD). After kidney transplantation, patients live
longer and experience a better quality of life (QoL) (Vo et al. 2013; Orandi et
al. 2016). More than 30% of all patients waiting for a kidney transplant have
developed antibodies of immunoglobulin G (IgG) type directed against foreign
human leukocyte antigen (HLA) (Orandi et al. 2016). The main causes for this
are previous organ transplantation, blood transfusion, infections, and
pregnancy. Patients with a wide range of HLA antibodies with high titres,
generating a calculated panel-reactive antibody (cPRA) value of >95%, are
considered highly unlikely to be transplanted since the chance of finding an
immunologically HLA-compatible donor is extremely low (EUROSTAM 2018).
Several therapeutic approaches have been tested to achieve desensitisation
(Marfo et al. 2011), though many patients do not respond adequately to
facilitate transplantation (Glotz et al. 2019; Sharma et al. 2016; Amrouche et
al. 2017; Kute et al. 2011; Vo et al. 2008; Bartel et al. 2010; Marfo et al.
2012; Schwaiger et al. 2016). However, the treatments referred to, and other
treatments in the literature, are experimental and are neither approved nor
considered standard of care across the transplant community for the patient
population to be included in the present trial, which is the patient population
with the greatest unmet medical need. Currently, highly sensitised patients
without a compatible living donor are placed on
the waiting list and stay there for many years until they are delisted due to
worsened comorbidity or death (Stewart et al. 2016; Schinstock et al. 2017).
The number of patients highly unlikely to receive a kidney transplant is
estimated to be approximately 3000 in the EU (EUROSTAM 2018). These patients
have an unmet medical need of a rapid, effective, and safe treatment to reduce
the HLA antibodies, more specifically donor specific antibodies (DSA), to
levels that would make them eligible for deceased donor kidney transplantation.
Imlifidase was developed to meet this need and has been shown to remove DSA and
convert positive crossmatch to negative in all highly sensitised patients
treated so far (Jordan et al. 2017; Lorant et al. 2018; Lonze et al. 2018;
Jordan et al. 2020).
Study objective
This study has been transitioned to CTIS with ID 2024-511810-18-00 check the CTIS register for the current data.
Primary objective
• To determine the 1-year graft failure-free survival in highly sensitised
kidney transplant patients, pre-treated with imlifidase to turn a positive
crossmatch against a deceased donor negative
Secondary objectives relating to imlifidase treatment group
• To evaluate renal function up to 1 year after transplantation
• To evaluate patient survival 1 year after transplantation
• To evaluate graft survival 1 year after transplantation
• To evaluate crossmatch conversion within 24 hours of imlifidase treatment
• To evaluate HLA/DSA antibody levels up to 1 year after transplantation
• To evaluate pharmacokinetic (PK) profile of imlifidase
• To evaluate pharmacodynamic (PD) profile of imlifidase
• To evaluate immunogenicity profile of imlifidase (anti-drug antibodies [ADAs])
• To evaluate delayed graft function (DGF)
• To evaluate proportion of patients with biopsy- and serology-confirmed
Antibody-Mediated Rejections (AMRs) up to 1 year after transplantation
• To evaluate proportion of patients with biopsy confirmed Cell-Mediated
Rejections (CMRs) up to 1 year after transplantation
• To evaluate safety of imlifidase treatment with regards to reported serious
adverse events (SAEs)
• To evaluate safety of imlifidase treatment with regards to infusion related
reactions occurring within 48 hours of imlifidase infusion
• To evaluate safety of imlifidase treatment with regards to severe or serious
infections occurring within 30 days after transplantation
• To evaluate health related quality of life (HRQoL) specifically patients*
life participation
Secondary Objectives relating to the non-comparative concurrent reference cohort
• To evaluate graft failure-free survival 1 year after transplantation
• To evaluate renal function up to 1 year after transplantation
• To evaluate patient survival 1 year after transplantation
• To evaluate graft survival 1 year after transplantation
• To evaluate DGF
• To evaluate proportion of patients with biopsy- and serology-confirmed AMRs
up to 1 year after transplantation
• To evaluate proportion of patients with biopsy confirmed CMRs up to 1 year
after transplantation
• To evaluate number of reported SAEs up to 1 year after transplantation
• To evaluate proportion of patients with severe or serious infections within
30 days after transplantation
• To evaluate health related quality of life (HRQoL) specifically patients*
life participation
Secondary Objectives relating to the randomly selected non-comparative
historical reference cohort retrieved from the CTS registry
• To evaluate graft survival 1 year after transplantation
• To evaluate renal function up to 1 year after transplantation
• To evaluate patient survival 1 year after transplantation
• To evaluate proportion of patients with rejection episodes during the first
posttransplant year in patients with a functioning graft at the end of the
first posttransplant year
Exploratory objective relating to the imlifidase treatment group and the
concurrent reference cohort
• To evaluate HRQoL, specifically patients* anxiety, depression, fatigue, pain
interference, physical function and sleep disturbance, self-reported
ability to work, and general health status
Study design
This is an open label, non-randomised trial in highly sensitised adult kidney
transplant patients with positive crossmatch against an available deceased
donor. 50 patients will be desensitised with imlifidase to convert a positive
crossmatch to negative and then transplanted. The patients will receive 0.25
mg/kg imlifidase intravenously (IV) over a period of 15 minutes. One dose is
adequate for most patients for crossmatch conversion, but if needed, a second
dose may be administered within 24 hours. Following transplantation, patients
will receive induction therapies (corticosteroids rabbit ATG), rejection
prophylaxis (high-dose intravenous immunoglobulin (IVIg), rituximab or
biosimilar) and maintenance immunosuppressive therapies. The patients will be
followed for 12 months and evaluation of graft failure-free survival 1 year
after transplantation is the primary objective. Other efficacy variables
include renal function, patient survival, graft survival, crossmatch
conversion, HLA/DSA levels, and health related quality-of-life. Safety
variables include rejection episodes, adverse events of special interest (i.e.,
imlifidase infusion-related reactions and
severe or serious infections), and serious adverse events (SAEs). Imlifidase
pharmacokinetics, pharmacodynamics and immunogenicity will also be investigated.
Patients who, for any reason, are not transplanted after imlifidase treatment
will not receive any post-transplantation therapy. All patients who receive
imlifidase will remain in the trial and will be followed in accordance with the
trial protocol even if they are not transplanted or if they lose their graft
during the course of the trial. To compensate non-transplanted imlifidase
patients, additional patients will be recruited in order to have 50 treated and
transplanted patients.
Important clinical outcomes are 1-year graft failure-free survival and kidney
function which reflect not the efficacy of imlifidase per se but effectiveness
and safety in the real-world transplantation setting. However, it should be
noted that this outcome is highly dependent on
the post-transplantation management of the patients, as well as compliance with
respect to maintenance immunosuppressive regimen.
The rational for performing a non-randomised trial is that no other effective
or approved desensitisation protocol exists in deceased-donor kidney
transplantation that would provide a suitable control. In the absence of such
treatment, randomisation between imlifidase and no imlifidase treatment
(control) would randomise patients with a positive crossmatch to a
nonconverting treatment, thus not allowing transplantation in these patients,
and preventing comparison of transplant outcome.
Instead, a non-comparative reference cohort consisting of 50 to 100 concurrent
kidney transplanted patients from participating trial sites with any grade of
sensitisation and a negative crossmatch towards their donor will be enrolled in
the trial. The rationale for including the non-comparative, prospective,
reference group is to address differences in-site practice and experience that
may have an impact on the overall results for the imlifidasetreated cohort.
Also, the difference in the extent of immunosuppressive therapies given in the
two cohorts will be addressed. Once a highly sensitised imlifidase treated
patient has been transplanted subsequent patients who are offered a compatible
kidney will also be offered the opportunity to be included in the trial as part
of the reference group and transplanted. The goal is to have at least 1 or 2
patients per imlifidase treated patient from each site participate in the
concurrent control group. Given that the patients in this reference cohort will
be qualitatively different from the imlifidase treated patients, formal
statistical comparisons will not be appropriate. Hence, data from these
patients will be collected for descriptive purposes only. Following completion
of the trial, and where possible, patients will be matched in terms of
relevant, baseline prognostic factors that can have an influence on graft and
patient survival. The concurrent control patients will be followed for 12
months after transplantation
(5 clinic visits) and treated in accordance with each clinic*s normal
transplantation routines. Efficacy variables followed in this cohort include
graft failure-free survival, patient survival, graft survival, renal function
and health related quality of life. The safety variables include
rejection episodes, adverse events of special interest (i.e., severe or serious
infections), and SAEs.
A second, non-comparative historical reference cohort of 100 kidney
transplanted patients will be randomly selected from the Collaborative
Transplant Study (CTS) registry. These patients will be less sensitised (cut
off PRA >=50%) compared to the current imlifidase cohort, have a negative
crossmatch towards their donor and by that have been transplanted. However,
outcome variables investigated in this cohort including 1-year graft survival,
renal function, patient survival and assessments of rejection episodes during
the first year will address the outcome in a sensitized cohort even though less
sensitised than in the imlifidase treatment group. 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 ELITE-Symphony trial investigated the 1-year eGFR with different
maintenance immunosuppression treatments (Ekberg et al. 2007). This publication
had a major impact on the transplant community and moved the general
immunosuppression towards primary use of low dose tacrolimus together with
prednisolone and mycophenolate mofetil (MMF). The year 2010 was chosen as
cut-off for inclusion in the 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.
Intervention
Imlifidase will be administered as a single IV infusion, 0.25 mg/kg, over a
period of 15 minutes. A second dose may be administered within 24 hours of the
first dose if the first dose is considered to have insufficient effect. The
transplant needs to occur within 24h after imlifidase treatment.
Study burden and risks
Patients in this trial are highly sensitised with the highest unmet medical
need, unlikely to be transplanted under the available kidney allocation system
including prioritisation programmes for highly sensitised patients. These
patients may benefit from being treated with imlifidase to remove HLA
antibodies and enable kidney transplantation. The potential benefit of
imlifidase over currently used methods for desensitisation includes the
extremely efficient inactivation of HLA antibodies including DSAs also for
patients who are highly sensitised with high antibody concentrations. This will
enable transplantation in a patient group with virtually no other options.
To date, a total of 46 patients in clinical studies have been transplanted
after treatment with imlifidase. Imlifidase was well-tolerated, with only few
related adverse events (AEs) reported and no clinically significant safety
findings.
Taking into account the measures taken to minimise risk to patients
participating in this clinical trial, the potential risks identified in
association with imlifidase treatment are justified by the anticipated benefits
that may be offered to highly sensitised patients waiting for a kidney
transplant.
Scheelevägen 22
Lund SE-220 07
SE
Scheelevägen 22
Lund SE-220 07
SE
Listed location countries
Age
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
3. Signed Informed Consent obtained before any trial related procedures
4. Willingness and ability to comply with the protocol
Inclusion Criteria for imlifidase patients
1. End-stage renal disease (ESRD) active on the renal transplant waiting list
of a kidney
allocation system at the time of screening
2. High sensitisation with the highest unmet medical need unlikely to be
transplanted
under the available kidney allocation system including prioritisation
programmes for
highly sensitised patients (see table below for recommended reference
thresholds. Note: highest unmet medical need is per investigator's discretion)
3. Known DSA against an available deceased donor
4. Positive crossmatch test determined by Complement-Dependent Cytotoxicity
crossmatch (CDCXM) and/or Flow Cytometry Crossmatch (FCXM) against an
available deceased donor. If physical crossmatch tests are not practically
possible due
to lack of time, patients may be included on a Virtual Crossmatch (vXM)
predictive
of a positive crossmatch test.
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
Exclusion criteria
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. Suspicion of Covid-19 infection or positive 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 (including HBV, HCV, CMV, EBV, tuberculosis)
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.
10. Any other reason that, in the view of the investigator, precludes
transplantation
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) (including hepatitis B [HBV],
hepatitis C [HCV], cytomegalovirus [CMV], Epstein Barr Virus [EBV],
tuberculosis) 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-511810-18-00 |
| EudraCT | EUCTR2021-002640-70-NL |
| CCMO | NL79830.078.22 |