Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05385432 |
Other study ID # |
DR210298 - INSTEAD |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
Phase 3
|
First received |
|
Last updated |
|
Start date |
September 12, 2023 |
Est. completion date |
March 1, 2030 |
Study information
Verified date |
September 2023 |
Source |
University Hospital, Tours |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Induction therapy decreases the rate of acute allograft rejection in kidney transplant
recipients (KTRs) and is strongly recommended. Polyclonal lymphocyte-depleting antibodies and
interleukin-2 receptor (IL2R) antagonists are therefore widely used around the world, with a
leading position for rabbit anti-thymocyte globulin (rATG, Thymoglobulin®) and basiliximab
(Simulect®), respectively. The actual immunological risk of the sensitized KTRs without donor
specific antibodies (DSAs) is still debated. The benefit-risk equation of lymphocyte
depleting antibodies (versus IL2R antagonists) is not known in sensitized KTRs without DSAs.
This clinical trial will compare the efficacy and safety of basiliximab and rATG in
sensitized KTR without pre-existing DSAs detected by Luminex.
Description:
Kidney transplantation is the first-line treatment of end stage renal disease, improving life
expectancy and quality of life in comparison to dialysis. The success of transplantation is a
consequence of major advances, especially the development of efficient immunosuppressive
drugs. However, thousands of kidney transplants fail yearly around the world, and kidney
allograft failure is known as an important case of end-stage renal disease, leading to
increased morbidity, mortality and costs. To improve graft survival is therefore a priority,
especially in a context of organ shortage.
Many risk factors of kidney graft loss have been identified but alloimmune response remains
the first determinant of graft loss. This powerful donor specific immune response involves
numerous effectors that may be harmful to the graft, such as T and B lymphocytes and
antibodies. Those antibodies are mainly directed against human leucocyte antigens (HLA) and
DSAs can be detected and identified in serum of sensitized KTRs. Alloreactivity T-cells and
antibodies may induce distinct categories of acute and chronic graft damages. Lesions of
rejection, recognized on tissue fragments sampling by percutaneous ultrasound-guided core
needle graft biopsy, are classified and graded according to international Banff
classification that is regularly updated. Two categories of biopsy-proven acute rejections
(BPAR) are thus distinguished: T-cell mediated rejection (TCMR) and antibody-mediated
rejection (ABMR). TCMR is a well-known risk factor of graft loss and also associated with
subsequent de novo DSAs appearance. ABMR is considered as the first cause of kidney graft
loss. In contrast to TCMR, that is usually sensitive to steroids, no treatment is able to
completely block the production of DSA and reverse the process of ABMR, especially chronic
ABMR. Prevent appearance of DSA and subsequent ABMR is therefore a major concern to improve
kidney transplant outcome.
Appearance of DSA after transplantation (de novo DSA) depends mainly on number of HLA
mismatches between donor and recipient and level of immunosuppression. Regarding
immunosuppression, two clinical trials have reported an increased incidence of de novo DSA in
patients receiving a calcineurin inhibitor-free maintenance treatment. In addition, some
retrospective studies have suggested that mycophenolic acid would be more efficient to
prevent de novo DSA formation. Standard-of-care for maintenance immunosuppression is
therefore a combination of anticalcineurin (tacrolimus has widely replaced cyclosporin over
last two decades), mycophenolic acid (mycophenolate mofetil or enteric-coated mycophenolate
sodium) and steroids. Data about induction therapy (i.e. initial immunosuppressive treatment
given during the first post-transplantation week) and risk of de novo DSA and ABMR are
scarce.
Induction therapy is a pivotal component of the immunosuppressive treatment. It has decreased
the rate of acute allograft rejection in KTRs and is strongly recommended. Polyclonal
lymphocyte-depleting antibodies and interleukin-2 receptor (IL2R) antagonists are thus widely
used around the world, with a leading position for rabbit anti-thymocyte globulin (rATG,
Thymoglobulin®) and basiliximab (Simulect®), respectively. Today, these two induction
treatments are used in common practice in kidney transplantation (rATG since 1984 and
basiliximab since 2003). According to international KDIGO recommendations, IL2R antagonists
are the first-line induction therapy in low-immunological risk no sensitized recipients
(level 1, grade A), while immunosuppressive intensification using lymphocyte depletive agents
is warranted in high-immunological KTRs (level 2, grade A). This intensification is supported
by two randomized clinical trials that found rATG as more efficient to prevent acute
rejection in recipients with a high immunological risk.
The current concern is that the definition of "immunological risk" used in those studies and
international recommendations is no longer in line with current clinical practices. Indeed,
immunological risk was estimated by the number of previous transplantations, recipient age,
donor age, ethnicity, number of HLA mismatches and level of sensitization (calculated
panel-reactive antibodies (cPRA) > 30%), based on cytotoxicity and ELISA techniques.
Nowadays, highly sensitive single HLA-antigen flow bead (SAB) assays have replaced
cytotoxicity and ELISA techniques in all French histocompatibility laboratories to detect low
amounts of anti-HLA antibodies and accurately determine their specificity. It is therefore
possible to characterize with a great precision whether a KTR is sensitized (i.e. presence of
any anti-HLA antibody, irrespective of its specificity) and has anti-HLA antibody specific
for DSA. Hence, the broad use of SAB assays has split sensitized KTRs in two distinct groups:
those with at least one pre-transplant DSA, who have undoubtedly a high risk of BPAR and
graft loss, and those without DSA. The actual immunological risk of the sensitized KTRs
without DSA is still debated. Some studies have suggested that the presence of non-donor
specific anti-HLA antibodies would represent an intermediate risk for graft loss and antibody
mediated rejection and others that these antibodies did not affect graft outcome and risk of
BPAR. A prospective study that compared rATG and basiliximab has recently confirmed that rATG
should be used in sensitized KTRs with low amount of DSA detectable using SAB assay. Finally,
the benefit-risk equation of lymphocyte depleting antibodies (versus IL2R antagonists)
remains unknown only in sensitized KTRs without DSA.
Address this concern is very important because rATG has the potential to induce long lasting
CD4+ T-cell depletion which may last for many months or even for many years. This prolonged
CD4 T-cell lymphopenia has been shown to be associated with an increase of morbidity and
mortality after renal transplantation. Indeed, profound CD4 T-cell lymphopenia (i.e. less
than 200-/mm3) exposes to an increase of viral infection and rATG has been identified as a
risk factor for BK virus (BKv) replication and cytomegalovirus (CMV) infection. The increase
of the risk of post-transplant lymphoproliferative disorder and/or solid cancer in patients
treated with rATG compared to the use of IL2R antagonists is still under debate. Because of
the potential side effects related to rATG, the use of lymphocyte depleting agents should be
limited only to patients who may benefit from its use compared to IL2R antagonists. Some
kidney transplant centers have recently decided to use basiliximab instead of rATG in
sensitized KTR without DSA before transplantation, in order to decrease the risk of infection
and malignancies. Investigators puslished a monocentric case control study that suggested
that basiliximab was associated with an unusual high risk of rejection and DSA appearance in
this specific population. Similar alert regarding basiliximab has been recently reported in a
small prospective study even though lack of power precludes any definitive conclusions. The
prescription of induction treatment is currently heterogeneous according to the centers.
These results highlight the urgent need of a new clinical trial to compare basiliximab and
rATG in sensitized KTR without pre-existing DSAs.