Belatacept 3 Month Post Transplant Conversion Study
| Status: | Recruiting |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/27/2018 |
| Start Date: | July 2014 |
| End Date: | July 2023 |
| Contact: | Lorenzo Gallon, MD |
| Email: | l-gallon@northwestern.edu |
| Phone: | (312) 695-4457 |
Randomized Conversion Of Epstein-Barr Virus (EBV)+ Kidney Transplant Recipients Of Living Or Standard Criteria Donors At Three Months Post Transplantation To Belatacept With MPA Or Belatacept With Low-Dose Tacrolimus (50% Of Dose) Compared To Patients Remaining On Center Specific Standard Therapy Of Tacrolimus And MPA
This study is being done to investigate the impact of changing immunosuppressive medications
from tacrolimus (Prograf®) to belatacept (Nulojix®) between three (3) and six (6) months
after kidney transplantation. The immune system is the body's defense against infection and
other disease. After transplantation, the body sees the new organ as "foreign" and tries to
destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from
attacking the transplanted organ. The primary purpose of this research study is to evaluate
the effects of three (3) different immunosuppressive treatments on rejection in
post-transplant kidney recipients. This study will test whether switching from tacrolimus to
belatacept will improve long-term kidney function.
Three of the immunosuppressants used in this study- mycophenolic acid (MPA), mycophenolate
mofetil (MMF) and tacrolimus- are medications approved by the United States Food and Drug
Administration (FDA) to be used after transplant. All of these medications have been
routinely used in kidney recipients here at Northwestern University.
Belatacept (the "study drug") has been approved by the FDA for use at the time of transplant.
However, the use of belatacept in this study is considered investigational as it has not been
FDA approved for use beginning at 3 months after transplant.
This study will involve 51 adult kidney transplant recipients at Northwestern.
from tacrolimus (Prograf®) to belatacept (Nulojix®) between three (3) and six (6) months
after kidney transplantation. The immune system is the body's defense against infection and
other disease. After transplantation, the body sees the new organ as "foreign" and tries to
destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from
attacking the transplanted organ. The primary purpose of this research study is to evaluate
the effects of three (3) different immunosuppressive treatments on rejection in
post-transplant kidney recipients. This study will test whether switching from tacrolimus to
belatacept will improve long-term kidney function.
Three of the immunosuppressants used in this study- mycophenolic acid (MPA), mycophenolate
mofetil (MMF) and tacrolimus- are medications approved by the United States Food and Drug
Administration (FDA) to be used after transplant. All of these medications have been
routinely used in kidney recipients here at Northwestern University.
Belatacept (the "study drug") has been approved by the FDA for use at the time of transplant.
However, the use of belatacept in this study is considered investigational as it has not been
FDA approved for use beginning at 3 months after transplant.
This study will involve 51 adult kidney transplant recipients at Northwestern.
Immunosuppressive therapy with the calcineurin inhibitors (CNI) cyclosporine (CsA) and
Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically,
although extensively and effectively used for kidney transplantation and other solid organ
transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal
dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular
acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of
post-transplant renal dysfunction and it is characterized by an irreversible and progressive
tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and
arterioles. Attempts to minimize CNIs and their known toxicities have been marginally
successful due to unacceptable rates of acute rejection and drug toxicity. Patients are
converted to alternative immunosuppressive therapy related to CNI side effects including
neurotoxicity, nephrotoxicity, cardiovascular (HTN, hyperlipidemia), metabolic (NODAT), and
cosmetic side effects. Furthermore, this class of medications is associated also, by blocking
Interleukin 2 (IL2) production, with negative impact on regulatory T cells (Tregs) generation
(an important subpopulation of T helper cells that has been associated with positive
immunomodulation and donor specific hypo-responsiveness).
Until the approval of Belatacept for adult EBV+ renal transplant recipients, there have been
limited alternative immunosuppressive agents available to mitigate drug induced renal
impairment. The phase III drug trials of Belatacept in combination with MMF and
corticosteroids have resulted in significant and sustained improvement in glomerular
filtration rate (GFR) at one year through three years post transplant. The overall safety of
belatacept compared to cyclosporine in de novo transplant recipients was similar. However,
there was an increased rate and severity of early acute rejection and post-transplant
lymphoproliferative disorder (PTLD) of the central nervous system in patients treated with
belatacept.
In a phase II switch study conducted by Bristol Myers Squibb (BMS), the incidence of acute
rejection at 24 months post conversion was similar in patients remaining on CNI (4%) compared
to those converted to belatacept (7%). There were no reported cases of post-transplant
lymphoproliferative disorder (PTLD) in this patient population as of two years post
randomization. However, one belatacept patient from Mexico developed tuberculosis and there
were more non-serious fungal infections in the belatacept treated patients.
Mechanistically, CD28 (Cluster of Differentiation 28) and CTLA-4 (cytotoxic
T-lymphocyte-associated protein 4) are important for the function of regulatory T cells
(Tregs). Belatacept binds to CD80/CD86 (Cluster of Differentiation 80/Cluster of
Differentiation 86) ligands on antigen presenting cells (APCs) preventing CD28 to bind with
these ligands and deliver the costimulatory signal to activate the T Cell. CTLA-4 is a
related receptor expressed on activated T cells that also recognizes CD80/CD86 (Cluster of
Differentiation 80/Cluster of Differentiation 86) and is thus termed co-inhibitory. It
transmits both cell intrinsic and cell extrinsic negative signals that impair activation.
Investigation of the effect of early conversion to Belatacept at month 3 post-transplant on
the subpopulations of T cells and B cells and peripheral blood and allograft biopsy-derived
gene expression subpopulation profiles are planned. Optimization of the Belatacept
immunosuppressive regimen to achieve good long term renal function and improved graft
survival requires understanding the relationships of these cell populations to clinical
outcomes.
Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically,
although extensively and effectively used for kidney transplantation and other solid organ
transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal
dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular
acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of
post-transplant renal dysfunction and it is characterized by an irreversible and progressive
tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and
arterioles. Attempts to minimize CNIs and their known toxicities have been marginally
successful due to unacceptable rates of acute rejection and drug toxicity. Patients are
converted to alternative immunosuppressive therapy related to CNI side effects including
neurotoxicity, nephrotoxicity, cardiovascular (HTN, hyperlipidemia), metabolic (NODAT), and
cosmetic side effects. Furthermore, this class of medications is associated also, by blocking
Interleukin 2 (IL2) production, with negative impact on regulatory T cells (Tregs) generation
(an important subpopulation of T helper cells that has been associated with positive
immunomodulation and donor specific hypo-responsiveness).
Until the approval of Belatacept for adult EBV+ renal transplant recipients, there have been
limited alternative immunosuppressive agents available to mitigate drug induced renal
impairment. The phase III drug trials of Belatacept in combination with MMF and
corticosteroids have resulted in significant and sustained improvement in glomerular
filtration rate (GFR) at one year through three years post transplant. The overall safety of
belatacept compared to cyclosporine in de novo transplant recipients was similar. However,
there was an increased rate and severity of early acute rejection and post-transplant
lymphoproliferative disorder (PTLD) of the central nervous system in patients treated with
belatacept.
In a phase II switch study conducted by Bristol Myers Squibb (BMS), the incidence of acute
rejection at 24 months post conversion was similar in patients remaining on CNI (4%) compared
to those converted to belatacept (7%). There were no reported cases of post-transplant
lymphoproliferative disorder (PTLD) in this patient population as of two years post
randomization. However, one belatacept patient from Mexico developed tuberculosis and there
were more non-serious fungal infections in the belatacept treated patients.
Mechanistically, CD28 (Cluster of Differentiation 28) and CTLA-4 (cytotoxic
T-lymphocyte-associated protein 4) are important for the function of regulatory T cells
(Tregs). Belatacept binds to CD80/CD86 (Cluster of Differentiation 80/Cluster of
Differentiation 86) ligands on antigen presenting cells (APCs) preventing CD28 to bind with
these ligands and deliver the costimulatory signal to activate the T Cell. CTLA-4 is a
related receptor expressed on activated T cells that also recognizes CD80/CD86 (Cluster of
Differentiation 80/Cluster of Differentiation 86) and is thus termed co-inhibitory. It
transmits both cell intrinsic and cell extrinsic negative signals that impair activation.
Investigation of the effect of early conversion to Belatacept at month 3 post-transplant on
the subpopulations of T cells and B cells and peripheral blood and allograft biopsy-derived
gene expression subpopulation profiles are planned. Optimization of the Belatacept
immunosuppressive regimen to achieve good long term renal function and improved graft
survival requires understanding the relationships of these cell populations to clinical
outcomes.
Inclusion Criteria
1. Adult ≥ 18 years of age
2. Male or Female
3. EBV seropositive
4. Recipient of renal transplant from living or deceased donor
Exclusion Criteria
1. Recipients with EBV serostatus negative or unknown
2. History of acute rejection (AR) within 3 months prior to randomization
3. History of positive donor specific antibodies (DSA)
4. History of antibody mediated rejection
5. Positive T-cell lymphocytotoxic cross match
6. Proteinuria >1 g/day or > 0.5 g/day if diabetic
7. Rejection on 3 month post-transplant screening biopsy
8. BK nephropathy at 3 months post-transplant screening biopsy
9. Positive pregnancy test at the time of randomization in female of child bearing
potential
10. History of previous transplant
We found this trial at
1
site
Chicago, Illinois 60611
Principal Investigator: Lorenzo Gallon, MD
Phone: 312-695-4457
Click here to add this to my saved trials
