Main objective of the trial is to determine the effect of individualizing the immunosuppressive therapy based on baseline immune-risk stratification according to 2 new biomarkers (d-sp ELISPOT IFN-γ and donor/recipient HLA Eplet Mismatch…
ID
Source
Brief title
Condition
- Other condition
- Renal and urinary tract therapeutic procedures
Synonym
Health condition
nier transplantatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Composite end-point evaluated at 2 years of follow-up as a proportion of
patients that meet any of the following criteria: loss of renal function,
incidence of acute clinical rejection confirmed by biopsy (BPAR) and
development of dnDSA.
Secondary outcome
• Death at 24 months.
• Graft loss at 24 months.
• Incidence and severity of subclinical and chronic rejection (according to
protocol biopsies at 3 and 24 months).
• Incidence of opportunistic infections at 24 months.
• Incidence of metabolic disorders derived from treatment (diabetes mellitus,
dyslipidemia and HBP) at 24 months.
• Incidence of cardiovascular events at 24 months.
• Incidence of malignancy (cutaneous and non-cutaneous cancer) at 24 months.
• Proportion of patients who maintain the treatment according to the protocol
at the end of the follow-up.
• Changes in the immune response at 24 months according to biomarkers:
o Allogenic response (dn-DSA, d-sp IFN-γ ELISPOT , Memory B cell Elispot,
urine cytokines CXCL9 and CXCL10)
o Rejection risk of blood transcriptional profile, according to the KSORT test
o Antiviral cellular response against CMV, VEB, VBK, NKG2
• Proportion of patients with Serious adverse events related to study drugs.
Background summary
Kidney transplantation is the election treatment for patients with chronic
end-stage kidney disease (CKD), since it offers a greater benefit in patient
survival, a better quality of life and an economic saving compared to the rest
of renal replacement therapies. Despite the fact that the improvement in the
patient's clinical care, surgical capabilities, the appearance of powerful
immunosuppressants and the better knowledge of the biology of alloimmunity have
allowed the improvement of graft survival during the first year after
transplantation, mainly due to a reduction of acute rejection rates, long-term
allograft survival remains suboptimal. The process of progressive loss of the
renal graft is multi-causal, but the activation of the donor-specific
alloimmune response (d-sp), as well as the direct renal toxicity of the
immunosuppressants, play a fundamental role.
Currently, immunosuppressive strategies are based on high dose with maximum
effectiveness without taking into account the individual susceptibility of each
patient to reject or accept the graft (*one size fits all*).
At this moment the immune risk stratification of transplant patient candidates
is done via the assessment of primary alloimmune activation. The differences
between donor and recipient in the HLA system and preformed donor-specific
alloantibodies (DSA are examined.. However, the post-transplant monitoring of
the pharmacodynamic effect of immunosuppressive treatment is carried out
exclusively by indirect data, such as the plasma levels of immunosuppressive
drugs, the presence of lymphopenia, opportunistic infections or by the
appearance of graft dysfunction suggestive of rejection. Following this
paradigm, a large fraction of transplant patients have a high probability of
receiving excessive or insufficient immunosuppression, thus being exposed to a
high risk of infections and drug toxicity or, conversely, to transplant
rejection, respectively. For this reason there is a need for biomarkers that
can make a stratification before transplantation between patients with a high
and patients with a low risk of rejection. In this way, immunosuppression can
be dosed to size. This can be crucial to improve the current results of kidney
transplantation.
In summary, in order to minimize immunosuppression safely in the
post-transplant period, sensitive non-invasive biomarkers are needed to
stratify the risk of graft rejection beforehand and which could be used
iteratively after transplantation in a non-invasive manner. Thus, the
evaluation of preformed immune memory, both humoral through pre-transplant DSA,
and and the assessment of the risk of primary alloimmune activation using a
better donor/recipient HLA mismatching a the Eplet level could significantly
help transplant physicians regarding decision-making of the type and burden of
immunosuppression.
Study objective
Main objective of the trial is to determine the effect of individualizing the
immunosuppressive therapy based on baseline immune-risk stratification
according to 2 new biomarkers (d-sp ELISPOT IFN-γ and donor/recipient HLA Eplet
Mismatch), in a composite end-point made by the loss of renal function,
incidence of acute rejection and development of dnDSA at 2 years of follow-up
in LDKT patients as compared to patients who are managed according to standard
immunosuppression.
Secundary objectives:
• To assess whether the individualized stratification of immunological risk and
therapeutic optimization reduces patient:
o Mortality;
o Renal graft loss;
o Development of subclinical acute and chronic rejection assessed in
protocol biopsies at 3 and 24 months;
o Opportunistic infections;
o Metabolic diseases derived from treatment (diabetes mellitus, dyslipidemia
and hypertension) and malignancy (cutaneous and non-cutaneous cancer) after 2
years of follow-up;
• Economical savings derived of treatment decision-making according to refined
immune-risk stratification;
• Changes in the allogenic d-sp alloresponse throughout the 2 years of
follow-up using ancillary biomarkers such as dnDSA, d-sp IFN-γ and memory
B-cell ELISPOT, urinary cytokines (CXCL9/CXCL10), and the transcriptional
profile risk of rejection evaluated with the kidney solid-organ rejection test
(kSORT) as well as the evaluation of cellular antiviral responses against CMV,
EBV and VBK viruses.
Study design
This is a randomized, open-label study, with parallel groups, stratified
according to donor age. This is a prospective interventional study in which two
strategies for the determination of immunosuppressive treatment in kidney
transplant patients from a live donor with low immunological risk according to
solid phase antibody detection assays (cPRA up to 50% but absence of actual or
historical DSAs) and negative Flow-cytometry crossmatch (FCXM) are compared.
Patients are randomized in a 1: 1 ratio to receive one of two immunosuppressive
treatment strategies:
a) Experimental group (groups A), in which the immunosuppressive treatment of
the patients is determined according to the result of 2 immunological risk
biomarkers (d-sp IFN-γ ELISPOT assay and number of HLA Eplet mismatch at the
DRB1 and DQB1 loci),
b) Control group (group B), in which all patients receive the usual triple
immunosuppressive treatment, without taking into account the results of the two
biomarkers.
After signing the informed consent the screeningperiod starts, lasting up to 28
days. In this period the donor will also consent for blood draw for biomarker
testing. The transplanted patients will be followed in the study for 24 months
after transplantation. In this 24 months period the patient will have 8 study
visits.
Intervention
The following combinations of immunosuppressive medication will be provided in
this study:
• thymoglobulin, tacrolimus, mycophenolate mofetil and prednisone (arm A1);
• basixilimab, tacrolimus, mycophenolate mofetil and prednisone (arm A2);
• tacrolimus, mycophenolate mofetil and prednisone, in which prednisone is
discontinued after 3 months (arm A3);
• basixilimab, tacrolimus, mycophenolate mofetil and prednisone (arm B)
There are two treatment arms, arm A and arm B, in which arm A is subdivided in
three different combinations of immunosuppressive medications. When randomized
in arm A the results of the biomarker test will be guiding which treatment the
patient will receive (arm A1, A2 or A3). When randomized to arm B the results
of the biomarker test will be blinded. Arm B is the standard treatment patients
would normally receive after a kidney transplant.
In the study a biopsy will be performed at month 3 and month 24 to determine
the incidence and severity of subclinical and chronic rejection.
Study burden and risks
Kidney transplantation is the election treatment for patients with chronic
end-stage kidney disease (CKD). A large fraction of transplant patients have a
high probability of receiving excessive or insufficient immunosuppression, thus
being exposed to a high risk of infections and drug toxicity or, conversely, to
transplant rejection, respectively. Therefore, the need to individually adjust
the type and amount of immunosuppression to kidney transplant patients
according to biomarkers that allow a more accurate immune-risk assessment is
key to overcome current kidney transplant outcomes.
The immune suppressive medication used in this study is registered for
transplants. Based on 2 biomarker tests, it is possible to give patients a more
individually targeted immune suppressive regime. Patients are well monitored
for adverse reactions / rejection reactions during the study. Where necessary,
action is taken for the benefit of the patient.
Risks/burden associated with procedures:
- Blood draws: The risks of blood draws may include fainting, pain and/or
bruising. Rarely there may be an infection at the site of the
needle puncture.
- Kidney biopsy: Risks of biopsy include pain, discomfort and bleeding.
- ECG: redness or itching caused by sticky pads.
The following procedures are performed:
- Physical examination at all visit;
- Measurement vital signs at all visit:
- ECG at screening and visit 1;
- Blood draws at all visits (local lab 9 x, biomarkers 6 x);
- Kidney biopsy at month 3 and month 24 visit.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
• Male or female patients >= 18 years old.
• Recipients of a primary kidney transplant from a living non-HLA identical
donor (at least 1 HLA missmatch).
• Compatible ABO transplant.
• Patients with a calculated PRA (cPRA) <= 75% by solid-phase assays and
absence of donor-specific anti-HLA antibodies (DSA) against class I and class
II in an actual or historical screened sera.
• Written informed consent must be obtained before any assessment is performed.
• Women of child-bearing potential must use highly reliable contraceptive
methods (Pearl-Index <1) in order to avoid pregnancy during the entire duration
of the study and up to 6 weeks after the end of their treatment with
Mycophenolate Mofetil (MMF). Women of child-bearing potential include any woman
who has experienced menarche and who has not undergone successful surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral
oophorectomy) or who is not post-menopausal (defined as amenorrhea >= 12
consecutive months, or women who are receiving hormone replacement therapy with
a documented level of follicle stimulating hormone (FSH)> 35 mlU / ml). Women
of child-bearing potential must have a pregnancy test with a negative result in
the 72 hours prior to the start of the trial.
• Sexually active males (also vasectomized men) receiving MMF must use a condom
during MMF treatment and the following 90 days. Fertile partners must use an
effective method of contraception.
• Patients must agree not to donate blood during MMF treatment and for 6 weeks
thereafter. Males should not donate sperm during MMF treatment and up to 90
days after completion.
Exclusion criteria
• Patients with a calculated PRA (cPRA) > 75% by solid-phase assays and/or
presence of donor-specific anti-HLA antibodies (DSA) against class I and class
II in an actual or historical screened sera.
• Positive pre-transplant Cross Match test (either CDC or FCXM).
• Recipients of a deceased donors.
• HLA identical subjects
• Multi-organ transplant recipients or prior kidney transplant.
• Patients with one of the following diseases:
o Primary focal and segmental glomerulosclerosis
o Atypical Uremic Hemolytic Syndrome (aHUS) / Thrombotic Thrombocytopenic
Purpura.
• Patients with active infection with Hepatitis B virus (HBV) and / or active
infection with Hepatitis C virus (positive PCR result) at the time of
transplant.
• Patients with known HIV disease.
• Patients with active systemic infection that requires continuing antibiotic
treatment.
• Patients with malignancy of any organ system, with the exception of localized
excised skin cancer.
• Patients with severe anemia (hemoglobin <6g/dl), leukopenia (WBC <2500/mm3)
and/or thrombocitopenia (platelet count <80.000/mm3).
• Hemodynamically unstable patients, even if they have hemoglobin levels> 6g /
dl.
• Patients with intestinal pathology or severe diarrhea that may decrease
absorption according to medical criteria.
• Patients with known hypersensitivity to any of the drugs used in this study.
• Patients who have received any investigational drug in the 30 days prior to
their inclusion in this study.
• Women of child-bearing potential who do not agree to use reliable
contraceptive measures during the trial, who are pregnant, breast-feeding or
presents a positive pregnancy test at the time of inclusion in the study.
• Patients who are legally detained in an official institution.
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 |
|---|---|
| EudraCT | EUCTR2017-002293-39-NL |
| ClinicalTrials.gov | NCT03465397 |
| CCMO | NL71246.018.20 |