Tacrolimus/Everolimus Versus Tacrolimus/Enteric-Coated Mycophenolate Sodium
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 2/7/2015 |
| Start Date: | November 2012 |
| End Date: | December 2014 |
| Contact: | Lois Hanson, R.N. |
| Email: | lhanson2@med.miami.edu |
| Phone: | 305-355-5314 |
Randomized, Open-Label Trial of Tacrolimus/Everolimus vs. Tacrolimus/Enteric-Coated Mycophenolate Sodium to Prevent Biopsy-Proven Acute Rejection and Chronic Allograft Injury in Adult, Primary Kidney Transplantation
A recent therapeutic strategy following renal transplantation includes simultaneous use of
reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic,
antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with
the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and
chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to
more favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal
has also been used in the attempt to avoid well-known side effects while maintaining
favorable patient and graft survival.8-10 While the investigators center and numerous other
centers have also included single agent, antibody induction utilizing the lymphodepleting
polyclonal antibody rabbit anti-human thymocyte globulin (ATG), nondepleting human
anti-interleukin-2 receptor (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or
lymphodepleting humanized anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now
suggests that an even more effective induction strategy may include the combined use of more
than one induction agent (each with fewer doses than if used alone), with the goal of
bringing the kidney transplant recipient even closer (through more effectively timed
lymphodepletion) to an optimally immunosuppressed state, allowing further reduction in
long-term maintenance drug dosing.18-25 The investigators have now successfully used dual
ATG/Dac induction therapy in both kidney-alone23-24 and simultaneous kidney-pancreas (SPK)
transplantation,18-20 and a recent report from the investigators center of kidney-alone and
SPK recipients shows that the addition of anti-CD25 to ATG for induction therapy more
effectively delays the return of peripheral blood CD25+ cells.25 In the kidney-alone
recipient study 3 doses of ATG were combined with 2 doses of Dac for induction,23-24 vs. the
investigators previous studies utilizing single agent induction with 7 doses of ATG or 5
doses of Dac.4,16,17 Successful combination of ATG/basiliximab as dual induction in kidney
transplantation has also been reported elsewhere,21-22 along with equivalency in clinical
outcomes using daclizumab vs. basiliximab.13
reduced calcineurin inhibitor (CNI) dosing and maximized use of a non-nephrotoxic,
antiproliferative drug (inosine monophosphate dehydrogenase (IMPDH) or TOR inhibitor), with
the goals of reducing/avoiding CNI nephrotoxicity, the incidence of acute rejection, and
chronic allograft injury (CAI) (i.e., interstitial fibrosis/tubular atrophy), leading to
more favorable longer-term patient and graft survival.1-7 Early corticosteroid withdrawal
has also been used in the attempt to avoid well-known side effects while maintaining
favorable patient and graft survival.8-10 While the investigators center and numerous other
centers have also included single agent, antibody induction utilizing the lymphodepleting
polyclonal antibody rabbit anti-human thymocyte globulin (ATG), nondepleting human
anti-interleukin-2 receptor (CD25) monoclonal antibody daclizumab (Dac) or basiliximab, or
lymphodepleting humanized anti-CD52 monoclonal antibody alemtuzumab,11-17 evidence now
suggests that an even more effective induction strategy may include the combined use of more
than one induction agent (each with fewer doses than if used alone), with the goal of
bringing the kidney transplant recipient even closer (through more effectively timed
lymphodepletion) to an optimally immunosuppressed state, allowing further reduction in
long-term maintenance drug dosing.18-25 The investigators have now successfully used dual
ATG/Dac induction therapy in both kidney-alone23-24 and simultaneous kidney-pancreas (SPK)
transplantation,18-20 and a recent report from the investigators center of kidney-alone and
SPK recipients shows that the addition of anti-CD25 to ATG for induction therapy more
effectively delays the return of peripheral blood CD25+ cells.25 In the kidney-alone
recipient study 3 doses of ATG were combined with 2 doses of Dac for induction,23-24 vs. the
investigators previous studies utilizing single agent induction with 7 doses of ATG or 5
doses of Dac.4,16,17 Successful combination of ATG/basiliximab as dual induction in kidney
transplantation has also been reported elsewhere,21-22 along with equivalency in clinical
outcomes using daclizumab vs. basiliximab.13
A. Primary Objectives:
1. The percentage of patients who develop chronic allograft injury (CAI) progression
during the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA
at either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).
2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months
post-transplant.
B. Secondary Objectives:
1. Adverse events including graft loss (death-censored and death-uncensored), and death at
12 months post-transplant.
2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful
review of all clinically indicated and protocol biopsies.
3. Renal function as determined by serum creatinine and estimated glomerular filtration
rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months
post-transplant. Use of multivariable analysis to compare renal function as well as
BPAR and CAI progression will also be performed (particularly, after adjusting for the
significant effects of donor age, recipient age, race/ethnicity, and any other
predictors).
5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study
medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT),
infections requiring hospitalization, and requirement of anti-lipid medication at 12 months
post-transplant.
6. Avoidance of the requirement for maintenance corticosteroid therapy after renal
transplantation.
7. Allowance of reduced maintenance tacrolimus dosing (rTd).
1. The percentage of patients who develop chronic allograft injury (CAI) progression
during the first 12 months post-transplant protocol biopsy (i.e., higher grade of IF/TA
at either the 6 or 12 month protocol biopsy in comparison with the baseline biopsy).
2. The incidence rate of biopsy-proven acute rejection (BPAR) during the first 12 months
post-transplant.
B. Secondary Objectives:
1. Adverse events including graft loss (death-censored and death-uncensored), and death at
12 months post-transplant.
2. Incidence rate and severity (severity of CAI at 12 months as well), based upon careful
review of all clinically indicated and protocol biopsies.
3. Renal function as determined by serum creatinine and estimated glomerular filtration
rate (eGFR) (calculated using the abbreviated MDRD formula) at 12, months
post-transplant. Use of multivariable analysis to compare renal function as well as
BPAR and CAI progression will also be performed (particularly, after adjusting for the
significant effects of donor age, recipient age, race/ethnicity, and any other
predictors).
5. Adverse events including withholding (for ≥ 28 days) or discontinuance of study
medications (and reasons why), new onset diabetes mellitus after transplantation (NODAT),
infections requiring hospitalization, and requirement of anti-lipid medication at 12 months
post-transplant.
6. Avoidance of the requirement for maintenance corticosteroid therapy after renal
transplantation.
7. Allowance of reduced maintenance tacrolimus dosing (rTd).
Inclusion Criteria:
- Weight > 40 kg.
- Deceased donor (SCD) or LD.
- Donor-recipient 1 haplotype matched pairs with a minimum matching of 1 HLA DR
antigen.
- Negative standard cross match for T cells.
- Pretransplant panel reactive antibodies of < 30%.
Exclusion Criteria:
- Previously received or is receiving an organ transplant other than a kidney.
- Donor organ with a cold ischemic time > 48 hours.
- ABO incompatible donor kidney.
- Recipients of T cell, or B cell crossmatch positive transplant.
- Panel reactive antibody (PRA) >30%
- HIV or Hepatitis C virus, or Hepatitis B virus antigenemia.
- Current malignancy or a history of malignancy
- Liver disease
- Uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper
gastro-intestinal tract malabsorption or an active peptic ulcer
- Use of warfarin, fluvastatin, or herbal supplements during the study.
- Use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole.
- Hypersensitivity to thymoglobulin, IL-2 receptor inhibitor monoclonal antibodies,
tacrolimus, everolimus, MPA, or corticosteroids.
- Pregnant or lactating.
- Abnormal screening/baseline labs WBC, platelet count, triglycerides, and cholesterol
Double kidneys,ECD, pediatric en-block, and donation after cardiac death (DCD)
We found this trial at
1
site
University of Miami A private research university with more than 15,000 students from around the...
Click here to add this to my saved trials
